Antibodies for epidermal growth factor receptor 3 (her3) directed to domain iii and domain iv of her3

ABSTRACT

The present invention relates to antibodies or fragments thereof that bind to a non-linear epitope within domain 3 of the HER3 receptor and inhibit both ligand-dependent and ligand-independent signal transduction. The invention also relates antibodies or fragments thereof that bind to amino acid residues within domains 3-4 of HER3 and inhibit both ligand-dependent and ligand-independent signal transduction; and compositions and methods of use of such antibodies or fragments thereof.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/566,912 filed on Dec. 5, 2011, the contents of which are incorporatedherein by reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Apr. 2, 2013, isnamed PAT054914-US-NP_SL.txt and is 561,528 bytes in size.

FIELD OF THE INVENTION

The present invention relates to antibodies or fragments thereof thatbind to a non-linear epitope within domain 3 of the HER3 receptor andinhibit both ligand-dependent and ligand-independent signaltransduction. The invention also relates antibodies or fragments thereofthat bind to amino acid residues within domains 3-4 of HER3 and inhibitboth ligand-dependent and ligand-independent signal transduction; andcompositions and methods of use of such antibodies or fragments thereof.

BACKGROUND OF THE INVENTION

The human epidermal growth factor receptor 3 (ErbB3, also known as HER3)is a receptor protein tyrosine kinase and belongs to the epidermalgrowth factor receptor (EGFR) subfamily of receptor protein tyrosinekinases, which also includes EGFR (HER1, ErbB1), HER2 (ErbB2, Neu), andHER4 (ErbB4) (Plowman et al., (1990) Proc. Natl. Acad. Sci. U.S.A.87:4905-4909; Kraus et al., (1989) Proc. Natl. Acad. Sci. U.S.A.86:9193-9197; and Kraus et al., (1993) Proc. Natl. Acad. Sci. U.S.A.90:2900-2904). Like the prototypical epidermal growth factor receptor,the transmembrane receptor HER3 consists of an extracellularligand-binding domain (ECD), a dimerization domain within the ECD, atransmembrane domain, an intracellular protein tyrosine kinase-likedomain (TKD) and a C-terminal phosphorylation domain. Unlike the otherHER family members, the kinase domain of HER3 displays very lowintrinsic kinase activity.

The ligands neuregulin 1 (NRG) or neuregulin 2 bind to the extracellulardomain of HER3 and activate receptor-mediated signaling pathway bypromoting dimerization with other dimerization partners such as HER2.Heterodimerization results in activation and transphosphorylation ofHER3's intracellular domain and is a means not only for signaldiversification but also signal amplification. In addition, HER3heterodimerization can also occur in the absence of activating ligandsand this is commonly termed ligand-independent HER3 activation. Forexample, when HER2 is expressed at high levels as a result of geneamplification (e.g. in breast, lung, ovarian or gastric cancer)spontaneous HER2/HER3 dimers can be formed. In this situation theHER2/HER3 is considered the most active ErbB signaling dimer and istherefore highly transforming.

Increased HER3 has been found in several types of cancer such as breast,lung, gastrointestinal and pancreatic cancers. Interestingly, acorrelation between the expression of HER2/HER3 and the progression froma non-invasive to an invasive stage has been shown (Alimandi et al.,(1995) Oncogene 10:1813-1821; DeFazio et al., (2000) Cancer 87:487-498;Naidu et al., (1988) Br. J. Cancer 78:1385-1390). Accordingly, agentsthat interfere with HER3 mediated signaling are needed.

SUMMARY OF THE INVENTION

The invention is based on the surprising discovery of antibodies orfragments thereof that bind to a non-linear epitope of HER3 receptorcomprising amino acid residues within domain 3 of HER3 and block bothligand-dependent (e.g. neuregulin) and ligand-independent HER3 signalingpathways. The invention is also based on the discovery of antibodies orfragments thereof that bind to amino acid residues within domains 3-4 ofHER3 and block both ligand-dependent (e.g. neuregulin) andligand-independent HER3 signaling pathways.

Accordingly, in one aspect, the invention pertains to an isolatedantibody or fragment thereof that recognizes a non-linear epitope of aHER3 receptor, wherein the non-linear epitope comprises amino acidresidues within domain 3 of the HER3 receptor, wherein the antibody orfragment thereof binds to binding surface B, and wherein the antibody orfragment thereof blocks both ligand-dependent and ligand-independentsignal transduction.

In one embodiment, binding surface B comprises at least one amino acidresidue selected from a group consisting of amino acid residues 335-342,398, 400, 424-428, 431, 433-434 and 455. In another embodiment, theantibody or fragment thereof further binds to binding surface A. In oneembodiment, binding surface A comprises at least one amino acid residueselected from a group consisting of amino acid residues 362-376.

In another aspect, the invention pertains to an isolated antibody orfragment thereof that recognizes a non-linear epitope of a HER3receptor, wherein the non-linear epitope comprises amino acid residueswithin domain 3 of the HER3 receptor, wherein the antibody or fragmentthereof binds to a binding surface comprising at least one amino acidresidue selected from binding surface A and at least one amino acidresidue selected from binding surface B, and wherein the antibody orfragment thereof blocks both ligand-dependent and ligand-independentsignal transduction.

In one embodiment, the antibody or fragment thereof blocks HER3 ligandbinding on the HER3 receptor. In one embodiment, the HER3 ligand isselected from the group consisting of neuregulin 1 (NRG), neuregulin 2,betacellulin, heparin-binding epidermal growth factor, and epiregulin.In one embodiment, the antibody or fragment thereof has any one of thecharacteristics selected from the group consisting of binding to theinactive state of the HER3 receptor, preventing HER3 adopting an activeconformation due to steric hindrance between the antibody or fragmentthereof and domains of HER3, preventing HER3 adopting an activeconformation by reducing the degree of flexibility in domain 3, inducinga conformational change in domain 3 residues 371-377 that prevents HER3from adopting an active conformation, destabilizing HER3 such that it issusceptible to degradation, accelerating down regulation of cell surfaceHER3, and generating an un-natural HER3 dimer that is susceptible toproteolytic degradation or unable to dimerize with other receptortyrosine kinases. In one embodiment, binding surface A comprises aminoacid residues 362-376. In one embodiment, binding surface B comprisesamino acid residues 335-342, 398, 400, 424-428, 431, 433-434 and 455.

In one embodiment, the non-linear epitope comprises amino acid residues335-342, 362-376, 398, 400, 424-428, 431, 433-434 and 455 (within domain3), or a subset thereof. In one embodiment, the VH of the antibody orfragment thereof binds to at least one of the following HER3 residues:Ile365, Thr366, Asn369, Gly370, Asp371, Pro372, Trp373, His374, Lys375,Gln400, and Lys434. In one embodiment, the VL of the antibody orfragment thereof binds to at least one of the following HER3 residues:Gly335, Ser336, Gly337, Ser338, Phe340, Gln341, Asp362, Leu364, Ile365,Thr366, His374, Ile376, Asn398, Gln400, Tyr424, Asn425, Arg426, Phe428,Leu431, Met433, Lys434, Tyr455. In one embodiment, binding of theantibody or fragment thereof to the HER3 receptor in the absence of aHER3 ligand reduces ligand-independent formation of a HER2-HER3 proteincomplex in a cell which expresses HER2 and HER3. In one embodiment, theantibody or fragment thereof inhibits phosphorylation of HER3 asassessed by a HER3 ligand-independent phosphorylation assay. In oneembodiment, the HER3 ligand-independent phosphorylation assay uses HER2amplified cells, wherein the HER2 amplified cells are SK-Br-3 cells andBT-474. In one embodiment, binding of the antibody or fragment thereofto the HER3 receptor in the presence of a HER3 ligand reducesligand-dependent formation of a HER2-HER3 protein complex in a cellwhich expresses HER2 and HER3. In one embodiment, the antibody orfragment thereof inhibits phosphorylation of HER3 as assessed by HER3ligand-dependent phosphorylation assay. In one embodiment, the HER3ligand-dependent phosphorylation assay uses stimulated MCF7 cells in thepresence of neuregulin (NRG). In one embodiment, the antibody isselected from the group consisting of a monoclonal antibody, apolyclonal antibody, a chimeric antibody, a humanized antibody, and asynthetic antibody.

In another aspect, the invention pertains to isolated antibody orfragment thereof that recognizes an epitope of a HER3 receptor, whereinthe epitope comprises amino acid residues within domains 3-4 of the HER3receptor, and wherein the antibody or fragment thereof blocks bothligand-dependent and ligand-independent signal transduction.

In one embodiment, the epitope comprises at least one amino acid residueselected from the group consisting of amino acid residues: 329-498(domain 3) of SEQ ID NO: 1, and at least one amino acid residue selectedfrom the group consisting of amino acid residues 499-642 (domain 4) ofSEQ ID NO: 1. In one embodiment, the epitope comprising amino acidresidues within domains 3-4 is selected from the group consisting of alinear epitope, a non-linear epitope, and a conformational epitope. Inone embodiment, binding of the antibody or fragment thereof to the HER3receptor in the absence of a HER3 ligand reduces ligand-independentformation of a HER2-HER3 protein complex in a cell which expresses HER2and HER3. In one embodiment, the antibody or fragment thereof inhibitsphosphorylation of HER3 as assessed by a HER3 ligand-independentphosphorylation assay. In one embodiment, the HER3 ligand-independentphosphorylation assay uses HER2 amplified cells, wherein the HER2amplified cells are SK-Br-3 cells and BT-474. In one embodiment, bindingof the antibody or fragment thereof to the HER3 receptor in the presenceof a HER3 ligand reduces ligand-dependent formation of a HER2-HER3protein complex in a cell which expresses HER2 and HER3. In oneembodiment, the antibody or fragment thereof inhibits phosphorylation ofHER3 as assessed by HER3 ligand-dependent phosphorylation assay. In oneembodiment, the HER3 ligand-dependent phosphorylation assay usesstimulated MCF7 cells in the presence of neuregulin (NRG).

In another aspect, the invention pertains to an isolated antibody orfragment thereof to a HER3 receptor, having a dissociation (K_(D)) of atleast 1×10⁷ M⁻¹, 10⁸ M⁻¹, 10⁹ M⁻¹, 10¹⁰ M⁻¹, 10¹¹ M⁻¹, 10¹² M⁻¹, 10¹³M⁻¹, wherein the antibody or fragment thereof blocks bothligand-dependent and ligand-independent signal transduction. In oneembodiment, the antibody or fragment thereof inhibits phosphorylation ofHER3 as measured by an in vitro phosphorylation assay selected from thegroup consisting of phospho-HER3 and phospho-Akt.

In another aspect, the invention pertains to an isolated antibody orfragment thereof binds to the same non-linear epitope within domain 3 ofHER3 as an antibody described in Table 1.

In another aspect, the invention pertains to an isolated antibody orfragment thereof, binds to the same amino acid residues within domains3-4 of HER3 as an antibody described in Table 2.

In another aspect, the invention pertains to a fragment of an antibodythat binds to HER3 selected from the group consisting of; Fab, F(ab₂)′,F(ab)₂′, scFv, VHH, VH, VL, dAbs, wherein the fragment of the antibodyblocks both ligand-dependent and ligand-independent signal transduction.

In another aspect, the invention pertains to a pharmaceuticalcomposition comprising an antibody or fragment thereof and apharmaceutically acceptable carrier. In one embodiment, thepharmaceutical composition further comprises an additional therapeuticagent. In one embodiment, the additional therapeutic agent is selectedfrom the group consisting of an HER1 inhibitor, a HER2 inhibitor, a HER3inhibitor, a HER4 inhibitor, an mTOR inhibitor and a PI3 Kinaseinhibitor. In one embodiment, the additional therapeutic agent is a HER1inhibitor selected from the group consisting of Matuzumab (EMD72000),Erbitux®/Cetuximab, Vectibix®/Panitumumab, mAb 806, Nimotuzumab,Iressa®/Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016),Tykerb®/Lapatinib Ditosylate, Tarceva®/Erlotinib HCL (OSI-774), PKI-166,and Tovok®; a HER2 inhibitor selected from the group consisting ofPertuzumab, Trastuzumab, MM-111, neratinib, lapatinib or lapatinibditosylate/Tykerb®; a HER3 inhibitor selected from the group consistingof, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203(Aveo), MEHD7945A (Genentech), MOR10703 (Novartis) and small moleculesthat inhibit HER3; and a HER4 inhibitor. In one embodiment, theadditional therapeutic agent is a HER3 inhibitor, wherein the HER3inhibitor is MOR10703. In one embodiment, the additional therapeuticagent is an mTOR inhibitor selected from the group consisting ofTemsirolimus/Torisel®, ridaforolimus/Deforolimus, AP23573, MK8669,everolimus/Affinitor®. In one embodiment, the additional therapeuticagent is a PI3 Kinase inhibitor selected from the group consisting ofGDC 0941, BEZ235, BKM120 and BYL719.

In one aspect, the invention pertains to a method of treating a cancercomprising selecting a subject having an HER3 expressing cancer,administering to the subject an effective amount of a compositioncomprising an antibody or fragment thereof disclosed in Table 1 or Table2. In one embodiment, the subject is a human and the cancer is selectedfrom the group consisting of breast cancer, colorectal cancer, lungcancer, multiple myeloma, ovarian cancer, liver cancer, gastric cancer,acute myeloid leukemia, chronic myeloid leukemia, osteosarcoma, squamouscell carcinoma, peripheral nerve sheath tumors, schwannoma, head andneck cancer, bladder cancer, esophageal cancer, Barretts esophagealcancer, glioblastoma, clear cell sarcoma of soft tissue, malignantmesothelioma, neurofibromatosis, renal cancer, and melanoma, prostatecancer, benign prostatic hyperplasia (BPH), gynacomastica, andendometriosis. In one embodiment, the cancer is breast cancer.

In one aspect, the invention pertains to use of the antibody or fragmentthereof for use as a medicament. In one aspect, the invention pertainsto use of the antibody or fragment thereof for use in treating a cancermediated by a HER3 ligand-dependent signal transduction orligand-independent signal transduction pathway. In one aspect, theinvention pertains to use of the antibody or fragment thereof for themanufacture of a medicament for the treatment of a cancer mediated by aHER3 ligand-dependent signal transduction or ligand-independent signaltransduction pathway selected from the group consisting of breastcancer, colorectal cancer, lung cancer, multiple myeloma, ovariancancer, liver cancer, gastric cancer, pancreatic cancer, acute myeloidleukemia, chronic myeloid leukemia, osteosarcoma, squamous cellcarcinoma, peripheral nerve sheath tumors, schwannoma, head and neckcancer, bladder cancer, esophageal cancer, Barretts esophageal cancer,glioblastoma, clear cell sarcoma of soft tissue, malignant mesothelioma,neurofibromatosis, renal cancer, melanoma, prostate cancer, benignprostatic hyperplasia (BPH), gynacomastica, and endometriosis.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 Representative MOR12615 SET curves obtained with human HER3;

FIG. 2 SK-Br-3 cell binding determination by FACS titration;

FIG. 3 HER3 domain binding ELISA;

FIG. 4 (A) Surface representation of the HER3/MOR12604 x-ray crystalstructure. HER3 (labeled by domains: D2, D3 & D4) is in the closedconformation, and MOR12604 binds to domain 3. (B) Cα-superposition ofHER3 from the HER3/MOR12064 structure (dark gray) with an unbound HER3structure (light gray; Cho et al., (2003) Nature 421:756-760) aligned bydomain 3. (C) View of the domain 3 epitope recognized by 12604.Highlighted HER3 residues are within 5A of MOR12604 in the x-ray crystalstructure (all positions disclosed in FIG. 4C are residues of SEQ ID NO:1). (D) View of domain 3/MOR12604 interaction. The MOR12604 bindingsurface is highlighted in dark gray with surface A (solid line) andsurface B (dashed line) indicated;

FIG. 5 Inhibition of ligand induced (A) HER3 and (B) Akt phosphorylationin MCF7 cells;

FIG. 6 Inhibition of ligand independent (A) HER3 and (B) Aktphosphorylation in HER2 amplified SKBr3 cells;

FIG. 7 Inhibition of ligand independent (A) HER3 and (B) Aktphosphorylation in HER2 amplified BT474 cells;

FIG. 8 Inhibition of ligand stimulated proliferation of MCF7 cells;

FIG. 9 Inhibition of ligand-independent proliferation of SKBr3 cells;

FIG. 10 Inhibition of ligand-independent proliferation of BT474 cells;

FIG. 11 Data showing inhibition of tumor growth in vivo in BxPC3 (A) andBT474 (B) using MOR12606 and MOR13655; and

FIG. 12 Data showing improved inhibition of tumor growth in vivo inBxPC3 using a combination of MOR12606 (DIII binder) and MOR10703 (DII+IVbinder).

DETAILED DESCRIPTION OF THE INVENTION Definitions

In order that the present invention may be more readily understood,certain terms are first defined. Additional definitions are set forththroughout the detailed description.

The phrase “signal transduction” or “signaling activity” as used hereinrefers to a biochemical causal relationship generally initiated by aprotein-protein interaction such as binding of a growth factor to areceptor, resulting in transmission of a signal from one portion of acell to another portion of a cell. For HER3, the transmission involvesspecific phosphorylation of one or more tyrosine, serine, or threonineresidues on one or more proteins in the series of reactions causingsignal transduction. Penultimate processes typically include nuclearevents, resulting in a change in gene expression.

The term “HER3” or “HER3 receptor” also known as “ErbB3” as used hereinrefers to mammalian HER3 protein and “her3” or “erbB3” refers tomammalian her3 gene. The preferred HER3 protein is human HER3 proteinpresent in the cell membrane of a cell. The human her3 gene is describedin U.S. Pat. No. 5,480,968 and Plowman et al., (1990) Proc. Natl. Acad.Sci. USA, 87:4905-4909.

Human HER3 as defined in Accession No. NP_(—)001973 (human), andrepresented below as SEQ ID NO: 1. All nomenclature is for full length,immature HER3 (amino acids 1-1342). The immature HER3 is cleaved betweenpositions 19 and 20, resulting in the mature HER3 protein (20-1342 aminoacids).

(SEQ ID NO: 1) mrandalqvl gllfslargs evgnsqavcp gtlnglsvtg daenqyqtlyklyercevvm gnleivltgh nadlsflqwi revtgyvlva mnefstlplp nlrvvrgtqvydgkfaifvm lnyntnssha lrqlrltqlt eilsggvyie kndklchmdt idwrdivrdrdaeivvkdng rscppchevc kgrcwgpgse dcqtltktic apqcnghcfg pnpnqcchdecaggcsgpqd tdcfacrhfn dsgacvprcp qplvynkltf qlepnphtky qyggvcvascphnfvvdqts cvracppdkm evdknglkmc epcgglcpka cegtgsgsrf qtvdssnidgfvnctkilgn ldflitglng dpwhkipald peklnvfrtv reitgylniq swpphmhnfsvfsnlttigg rslynrgfsl limknlnvts lgfrslkeis agriyisanr qlcyhhslnwtkvlrgptee rldikhnrpr rdcvaegkvc dplcssggcw gpgpgqclsc rnysrggvcvthcnflngep refaheaecf schpecqpme gtatcngsgs dtcaqcahfr dgphcvsscphgvlgakgpi ykypdvqnec rpchenctqg ckgpelqdcl gqtlvligkt hltmaltviaglvvifmmlg gtflywrgrr iqnkramrry lergesiepl dpsekankvl arifketelrklkvlgsgvf gtvhkgvwip egesikipvc ikviedksgr qsfqavtdhm laigsldhahivrllglcpg sslqlvtqyl plgslldhvr qhrgalgpql llnwgvqiak gmyyleehgmvhrnlaarnv llkspsqvqv adfgvadllp pddkqllyse aktpikwmal esihfgkythqsdvwsygvt vwelmtfgae pyaglrlaev pdllekgerl aqpqictidv ymvmvkcwmidenirptfke laneftrmar dpprylvikr esgpgiapgp ephgltnkkl eevelepeldldldleaeed nlatttlgsa lslpvgtlnr prgsqsllsp ssgympmnqg nlgescqesavsgssercpr pvslhpmprg clasessegh vtgseaelqe kvsmcrsrsr srsprprgdsayhsqrhsll tpvtplsppg leeedvngyv mpdthlkgtp ssregtlssv glssvlgteeededeeyeym nrrrrhspph pprpssleel gyeymdvgsd lsaslgstqs cplhpvpimptagttpdedy eymnrqrdgg gpggdyaamg acpaseqgye emrafqgpgh qaphvhyarlktlrsleatd safdnpdywh srlfpkanaq rt

The term “HER3 ligand” as used herein refers to polypeptides which bindand activate HER3. Examples of HER3 ligands include, but are not limitedto neuregulin 1 (NRG) and neuregulin 2, betacellulin, heparin-bindingepidermal growth factor, and epiregulin. The term includes biologicallyactive fragments and/or variants of a naturally occurring polypeptide.

The “HER2-HER3 protein complex” is a noncovalently associated oligomercontaining HER2 receptor and the HER3 receptor. This complex can formwhen a cell expressing both of these receptors is exposed to a HER3ligand e.g., NRG or when HER2 is active/overexpressed

The phrase “HER3 activity” or “HER3 activation” as used herein refers toan increase in oligomerization (e.g. an increase in HER3 containingcomplexes), HER3 phosphorylation, conformational rearrangements (forexample those induced by ligands), and HER3 mediated downstreamsignaling.

The term “stabilization” or “stabilized” used in the context of HER3refers to an antibody or fragment thereof that directly maintains(locks, tethers, holds, preferentially binds, favors) the inactive stateor conformation of HER3 without blocking ligand binding to HER3, suchthat ligand binding is no longer able to activate HER3.

The term “ligand-dependent signaling” as used herein refers to theactivation of HER3 via ligand. HER3 activation is evidenced by increasedheterodimerization and/or HER3 phosphorylation such that downstreamsignaling pathways (e.g. PI3K) are activated. The antibody or fragmentthereof can statistically significantly reduce the amount ofphosphorylated HER3 in a stimulated cell exposed to an antibody orfragment thereof relative to an untreated (control) cell, as measuredusing the assays described in the Examples. The cell which expressesHER3 can be a naturally occurring cell line (e.g. MCF7) or can berecombinantly produced by introducing nucleic acids encoding HER3protein into a host cell. Cell stimulation can occur either via theexogenous addition of an activating HER3 ligand or by the endogenousexpression of an activating ligand.

The antibody or fragment thereof which “reduces neregulin-induced HER3activation in a cell” is one which statistically significantly reducesHER3 tyrosine phosphorylation relative to an untreated (control) cell,as measured using the assays described in the Examples. This can bedetermined based on HER3 phosphotyrosine levels following exposure ofHER3 to NRG and the antibody of interest. The cell which expresses HER3protein can be a naturally occurring cell or cell line (e.g. MCF7) orcan be recombinantly produced.

The term “ligand-independent signaling” as used herein refers tocellular HER3 activity (e.g phosphorylation) in the absence of arequirement for ligand binding. For example, ligand-independent HER3activation can be a result of HER2 overexpression or activatingmutations in HER3 heterodimer partners such as EGFR and HER2. Theantibody or fragment thereof can statistically significantly reduce theamount of phosphorylated HER3 in a cell exposed to an antibody orfragment thereof relative to an untreated (control) cell. The cell whichexpresses HER3 can be a naturally occurring cell line (e.g. SK-Br-3) orcan be recombinantly produced by introducing nucleic acids encoding HER3protein into a host cell.

The term “blocks” as used herein refers to stopping or preventing aninteraction or a process, e.g., stopping ligand-dependent orligand-independent signaling.

The term “recognize” as used herein refers to an antibody or fragmentthereof that finds and interacts (e.g., binds) with its epitope indomain 3 of HER3; domain 4 of HER3; or both domain 3 and domain 4 ofHER3. The epitope can be a linear, non-linear, or conformationalepitope. For example, an antibody or fragment thereof interacts withamino acid residues: 335-342, 362-376, 398, 400, 424-428, 431, 433-434and 455 (within domain 3), or a subset thereof of HER3. In anotherexample, the antibody or fragment thereof interacts with at least oneamino acid residue selected from amino acid residues: 329-498 (domain3), or a subset thereof. In another example, the antibody or fragmentthereof interacts with at least one amino acid residue selected fromamino acid residues: 499-642 (domain 4), or a subset thereof. In anotherexample, the antibody or fragment thereof interacts with at least oneamino acid residue selected from domain 3 of HER3 (amino acid residues329-498 of SEQ ID NO: 1), and at least one amino acid residue selectedfrom domain 4 (amino acid residues 499-642 of SEQ ID NO: 1), or a subsetthereof.

The phrase “concurrently binds” as used herein refers to a HER3 ligandthat can bind to a ligand binding site on the HER3 receptor along withthe HER3 antibody or fragment thereof. This means that both the antibodyand ligand can bind to the HER3 receptor together. For the sake ofillustration only, the HER3 ligand NRG, can bind to the HER3 receptoralong with the HER3 antibody. Assay to measure concurrent binding of theligand and antibody are described in the Examples section.

The term “fails” as used herein refers to an antibody or fragmentthereof that does not do a particular event. For example, an antibody orfragment thereof that “fails to activate signal transduction” is onethat does not trigger signal transduction.

The term “antibody” as used herein refers to whole antibodies thatinteract with (e.g., by binding, steric hindrance,stabilizing/destabilizing, spatial distribution) an HER3 epitope andinhibit signal transduction. A naturally occurring “antibody” is aglycoprotein comprising at least two heavy (H) chains and two light (L)chains inter-connected by disulfide bonds. Each heavy chain is comprisedof a heavy chain variable region (abbreviated herein as VH) and a heavychain constant region. The heavy chain constant region is comprised ofthree domains, CH1, CH2 and CH3. Each light chain is comprised of alight chain variable region (abbreviated herein as VL) and a light chainconstant region. The light chain constant region is comprised of onedomain, CL. The VH and VL regions can be further subdivided into regionsof hypervariability, termed complementarity determining regions (CDR),interspersed with regions that are more conserved, termed frameworkregions (FR). Each VH and VL is composed of three CDRs and four FRsarranged from amino-terminus to carboxy-terminus in the following order:FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavyand light chains contain a binding domain that interacts with anantigen. The constant regions of the antibodies may mediate the bindingof the immunoglobulin to host tissues or factors, including variouscells of the immune system (e.g., effector cells) and the firstcomponent (C1q) of the classical complement system. The term “antibody”includes for example, monoclonal antibodies, human antibodies, humanizedantibodies, camelised antibodies, chimeric antibodies, single-chain Fvs(scFv), disulfide-linked Fvs (sdFv), Fab fragments, F (ab′) fragments,and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Idantibodies to antibodies of the invention), and epitope-bindingfragments of any of the above. The antibodies can be of any isotype(e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3,IgG4, IgA1 and IgA2) or subclass.

Both the light and heavy chains are divided into regions of structuraland functional homology. The terms “constant” and “variable” are usedfunctionally. In this regard, it will be appreciated that the variabledomains of both the light (VL) and heavy (VH) chain portions determineantigen recognition and specificity. Conversely, the constant domains ofthe light chain (CL) and the heavy chain (CH1, CH2 or CH3) conferimportant biological properties such as secretion, transplacentalmobility, Fc receptor binding, complement binding, and the like. Byconvention the numbering of the constant region domains increases asthey become more distal from the antigen binding site or amino-terminusof the antibody. The N-terminus is a variable region and at theC-terminus is a constant region; the CH3 and CL domains actuallycomprise the carboxy-terminus of the heavy and light chain,respectively.

The phrase “antibody fragment”, as used herein, refers to one or moreportions of an antibody that retain the ability to specifically interactwith (e.g., by binding, steric hindrance, stabilizing/destabilizing,spatial distribution) an HER3 epitope and inhibit signal transduction.Examples of binding fragments include, but are not limited to, a Fabfragment, a monovalent fragment consisting of the VL, VH, CL and CH1domains; a F(ab)₂ fragment, a bivalent fragment comprising two Fabfragments linked by a disulfide bridge at the hinge region; a Fdfragment consisting of the VH and CH1 domains; a Fv fragment consistingof the VL and VH domains of a single arm of an antibody; a dAb fragment(Ward et al., (1989) Nature 341:544-546), which consists of a VH domain;and an isolated complementarity determining region (CDR).

Furthermore, although the two domains of the Fv fragment, VL and VH, arecoded for by separate genes, they can be joined, using recombinantmethods, by a synthetic linker that enables them to be made as a singleprotein chain in which the VL and VH regions pair to form monovalentmolecules (known as single chain Fv (scFv); see e.g., Bird et al.,(1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad.Sci. 85:5879-5883). Such single chain antibodies are also intended to beencompassed within the term “antibody fragment”. These antibodyfragments are obtained using conventional techniques known to those ofskill in the art, and the fragments are screened for utility in the samemanner as are intact antibodies.

Antibody fragments can also be incorporated into single domainantibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies,tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005)Nature Biotechnology 23:1126-1136). Antibody fragments can be graftedinto scaffolds based on polypeptides such as Fibronectin type 111 (Fn3)(see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptidemonobodies).

Antibody fragments can be incorporated into single chain moleculescomprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, togetherwith complementary light chain polypeptides, form a pair of antigenbinding regions (Zapata et al., (1995) Protein Eng. 8:1057-1062; andU.S. Pat. No. 5,641,870).

The term “epitope” includes any protein determinant capable of specificbinding to an immunoglobulin or otherwise interacting with a molecule.Epitopic determinants generally consist of chemically active surfacegroupings of molecules such as amino acids or carbohydrate or sugar sidechains and can have specific three-dimensional structuralcharacteristics, as well as specific charge characteristics. An epitopemay be “linear,” “non-linear” or “conformational.”

The term “linear epitope” refers to an epitope with all of the points ofinteraction between the protein and the interacting molecule (such as anantibody) occur linearly along the primary amino acid sequence of theprotein (continuous). Once a desired epitope on an antigen isdetermined, it is possible to generate antibodies to that epitope, e.g.,using the techniques described in the present invention. Alternatively,during the discovery process, the generation and characterization ofantibodies may elucidate information about desirable epitopes. From thisinformation, it is then possible to competitively screen antibodies forbinding to the same epitope. An approach to achieve this is to conductcross-competition studies to find antibodies that competitively bindwith one another, e.g., the antibodies compete for binding to theantigen. A high throughput process for “binning” antibodies based upontheir cross-competition is described in International Patent ApplicationNo. WO 2003/48731. As will be appreciated by one of skill in the art,practically anything to which an antibody can specifically bind could bean epitope. An epitope can comprises those residues to which theantibody binds.

The term “non-linear epitope” refers to epitope with non-contiguousamino acids that form a three-dimensional structure within a particulardomain (e.g., within domain 1, within domain 2, within domain 3, orwithin domain 4). In one embodiment, the non-linear epitope is withindomain 2. The non-linear epitope may also occur between two or moredomains (e.g., the interface between domains 3-4). Non-linear epitopealso refers to non-contiguous amino acids that are a result of athree-dimensional structure within a particular domain.

The term “conformational epitope” refers to an epitope in whichdiscontinuous amino acids come together in a three dimensionalconfiguration. In a conformational epitope, the points of interactionoccur across amino acid residues on the protein that are separated fromone another in the sequence. As will be appreciated by one of skill inthe art, the space that is occupied by a residue or side chain thatcreates the shape of a molecule helps to determine what an epitope is.

In one embodiment, the epitope is within domain 3 of HER3. In oneembodiment, the epitope is a non-linear epitope comprising amino acidsresidues within domain 3 of HER3. In one embodiment, the non-linearepitope comprises amino acid residues: 335-342, 362-376, 398, 400,424-428, 431, 433-434 and 455 (within domain 3), or a subset thereof ofSEQ ID NO:1.

In another embodiment, the epitope is within domain 4 of HER3. In oneembodiment, the epitope comprises at least one amino acid residueselected from domain 4 (amino acid residues 499-642 of SEQ ID NO: 1), ora subset thereof. In one embodiment, the epitope is a linear epitopewithin domain 4 of HER3. In one embodiment, the epitope is a non-linearepitope within domain 4 of HER3. In another embodiment, the epitope is aconformational epitope within domain 4 of HER3.

In another embodiment, the epitope is within domains 3-4 of HER3. In oneembodiment, the epitope comprises at least one amino acid residueselected from domain 3 (amino acid residues 329-498 of SEQ ID NO: 1), ora subset thereof. In one embodiment, the epitope comprises at least oneamino acid residue selected from domain 4 (amino acid residues 499-642of SEQ ID NO: 1), or a subset thereof. In one embodiment, the epitopecomprises at least one amino acid residue selected from domain 3 (aminoacid residues 329-498 of SEQ ID NO: 1) and least one amino acid residueselected from domain 4 (amino acid residues 499-642 of SEQ ID NO: 1) ora subset thereof. In one embodiment, the epitope is a linear epitope. Inone embodiment, the epitope is a non-linear epitope. In anotherembodiment, the epitope is a conformational epitope.

Generally, antibodies specific for a particular target antigen willpreferentially recognize an epitope on the target antigen in a complexmixture of proteins and/or macromolecules. Regions of a givenpolypeptide that include an epitope can be identified using any numberof epitope mapping techniques, well known in the art. See, e.g., EpitopeMapping Protocols in Methods in Molecular Biology, Vol. 66 (Glenn E.Morris, Ed., 1996) Humana Press, Totowa, N.J. For example, linearepitopes may be determined by e.g., concurrently synthesizing largenumbers of peptides on solid supports, the peptides corresponding toportions of the protein molecule, and reacting the peptides withantibodies while the peptides are still attached to the supports. Suchtechniques are known in the art and described in, e.g., U.S. Pat. No.4,708,871; Geysen et al., (1984) Proc. Natl. Acad. Sci. USA 8:3998-4002;Geysen et al., (1985) Proc. Natl. Acad. Sci. USA 82:78-182; Geysen etal., (1986) Mol. Immunol. 23:709-715. Similarly, non-linear andconformational epitopes are readily identified by determining spatialconformation of amino acids such as by, e.g., hydrogen/deuteriumexchange, x-ray crystallography and two-dimensional nuclear magneticresonance. See, e.g., Epitope Mapping Protocols, supra. Antigenicregions of proteins can also be identified using standard antigenicityand hydropathy plots, such as those calculated using, e.g., the Omigaversion 1.0 software program available from the Oxford Molecular Group.This computer program employs the Hopp/Woods method, Hopp et al., (1981)Proc. Natl. Acad. Sci. USA 78:3824-3828; for determining antigenicityprofiles, and the Kyte-Doolittle technique, Kyte et al., (1982) J. Mol.Biol. 157:105-132; for hydropathy plots.

The term “binding surface” as used herein refers to multiple contiguousor non-contiguous surfaces in a 3D configuration on HER3, e.g., domain 3of HER3. These surfaces form part of the epitope and interact with anantibody or fragment thereof. For example, a binding surface cancomprise at least two surfaces (e.g., surface A and surface B, see FIG.4D), at least three surfaces (e.g., surface A, surface B, and surfaceC), at least four surfaces (e.g., surface A, surface B, surface C, andsurface D), at least five surfaces (e.g., surface A, surface B, surfaceC, surface D, and surface E), at least six surfaces (e.g., surface A,surface B, surface C, surface D, surface E, and surface F), at leastseven surfaces (e.g., surface A, surface B, surface C, surface D,surface E, surface F, and surface G), at least eight surfaces (e.g.,surface A, surface B, surface C, surface D, surface E, surface F,surface G, and surface H), at least nine surfaces (e.g., surface A,surface B, surface C, surface D, surface E, surface F, surface G,surface H, and surface I), or at least ten surfaces (e.g., surface A,surface B, surface C, surface D, surface E, surface F, surface G,surface H, surface I, and surface J).

The term “binding surface A” as used herein refers to a surface ondomain 3 of HER3 comprising at least one amino acid residue selectedfrom a group consisting of amino acid residues 362-376.

The term “binding surface B” as used herein refers to a surface ondomain 3 of HER3 comprising at least one amino acid residue selectedfrom a group consisting of amino acid residues 335-342, 398, 400,424-428, 431, 433-434 and 455.

The phrases “monoclonal antibody” or “monoclonal antibody composition”as used herein refers to polypeptides, including antibodies, antibodyfragments, bispecific antibodies, etc. that have substantially identicalto amino acid sequence or are derived from the same genetic source. Thisterm also includes preparations of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope.

The phrase “human antibody”, as used herein, includes antibodies havingvariable regions in which both the framework and CDR regions are derivedfrom sequences of human origin. Furthermore, if the antibody contains aconstant region, the constant region also is derived from such humansequences, e.g., human germline sequences, or mutated versions of humangermline sequences or antibody containing consensus framework sequencesderived from human framework sequences analysis, for example, asdescribed in Knappik et al., (2000) J Mol Biol 296:57-86). Thestructures and locations of immunoglobulin variable domains, e.g., CDRs,may be defined using well known numbering schemes, e.g., the Kabatnumbering scheme, the Chothia numbering scheme, or a combination ofKabat and Chothia (see, e.g., Sequences of Proteins of ImmunologicalInterest, U.S. Department of Health and Human Services (1991), eds.Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948); Kabatet al., (1991) Sequences of Proteins of Immunological Interest, 5thedit., NIH Publication no. 91-3242 U.S. Department of Health and HumanServices; Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia etal., (1989) Nature 342:877-883; and Al-Lazikani et al., (1997) J. Mol.Biol. 273:927-948.

The human antibodies of the invention may include amino acid residuesnot encoded by human sequences (e.g., mutations introduced by random orsite-specific mutagenesis in vitro or by somatic mutation in vivo, or aconservative substitution to promote stability or manufacturing).

The phrase “human monoclonal antibody” as used herein refers toantibodies displaying a single binding specificity which have variableregions in which both the framework and CDR regions are derived fromhuman sequences. In one embodiment, the human monoclonal antibodies areproduced by a hybridoma which includes a B cell obtained from atransgenic nonhuman animal, e.g., a transgenic mouse, having a genomecomprising a human heavy chain transgene and a light chain transgenefused to an immortalized cell.

The phrase “recombinant human antibody”, as used herein, includes allhuman antibodies that are prepared, expressed, created or isolated byrecombinant means, such as antibodies isolated from an animal (e.g., amouse) that is transgenic or transchromosomal for human immunoglobulingenes or a hybridoma prepared therefrom, antibodies isolated from a hostcell transformed to express the human antibody, e.g., from atransfectoma, antibodies isolated from a recombinant, combinatorialhuman antibody library, and antibodies prepared, expressed, created orisolated by any other means that involve splicing of all or a portion ofa human immunoglobulin gene, sequences to other DNA sequences. Suchrecombinant human antibodies have variable regions in which theframework and CDR regions are derived from human germline immunoglobulinsequences. In certain embodiments, however, such recombinant humanantibodies can be subjected to in vitro mutagenesis (or, when an animaltransgenic for human Ig sequences is used, in vivo somatic mutagenesis)and thus the amino acid sequences of the V_(H) and V_(L) regions of therecombinant antibodies are sequences that, while derived from andrelated to human germline V_(H) and V_(L) sequences, may not naturallyexist within the human antibody germline repertoire in vivo.

Specific binding between two entities means a binding with anequilibrium constant (K_(A)) (k_(on)/k_(off)) of at least 10²M⁻¹, atleast 5×10³M⁻¹, at least 10³M⁻¹, at least 5×10³M⁻¹, at least 10⁴M⁻¹ atleast 5×10⁴M⁻¹, at least 10⁵M⁻¹, at least 5×10⁵M⁻¹, at least 10⁶M⁻¹, atleast 5×10⁶M⁻¹, at least 10⁷M⁻¹, at least 5×10⁷M⁻¹, at least 10M⁻¹, atleast 5×10M⁻¹, at least 10⁹M⁻¹, at least 5×10⁹M⁻¹, at least 10¹⁰M⁻¹, atleast 5×10¹⁰M⁻¹, at least 10¹¹M⁻¹, at least 5×10¹¹M⁻¹, at least 10¹²M⁻¹,at least 5×10¹²M⁻¹, at least 10¹³M⁻¹, at least 5×10¹³M⁻¹, at least10¹⁴M⁻¹, at least 5×10¹⁴M⁻¹, at least 10¹⁵M⁻¹, or at least 5×10¹⁵M⁻¹.

The phrase “specifically (or selectively) binds” refers to a bindingreaction of a HER3 binding antibody and HER3 receptor in a heterogeneouspopulation of proteins and other biologics. In addition to theequilibrium constant (K_(A)) noted above, an HER3 binding antibody ofthe invention typically also has a dissociation rate constant (K_(D))(k_(off)/k_(on)) of less than 5×10⁻²M, less than 10⁻²M, less than5×10⁻³M, less than 10⁻³M, less than 5×10⁻⁴M, less than 10⁻⁴M, less than5×10⁻⁵M, less than 10⁻⁵M, less than 5×10⁻⁶M, less than 10⁻⁶M, less than5×10⁻⁷M, less than 10⁻⁷M, less than 5×10⁻¹⁰M, less than 10⁻⁸M, less than5×10⁻⁹M, less than 10⁻⁹M, less than 5×10⁻¹⁰M, less than 10⁻¹⁰M, lessthan 5×10⁻¹¹M, less than 1011M, less than 5×10⁻¹²M, less than 10⁻¹²M,less than 5×10⁻¹³M, less than 10⁻¹³M, less than 5×10⁻¹⁴M, less than10⁻¹⁴M, less than 5×10⁻¹⁵M, or less than 10⁻¹⁵M or lower, and binds toHER3 with an affinity that is at least two-fold greater than itsaffinity for binding to a non-specific antigen (e.g., HSA).

In one embodiment, the antibody or fragment thereof has dissociationconstant (K_(d)) of less than 3000 pM, less than 2500 pM, less than 2000pM, less than 1500 pM, less than 1000 pM, less than 750 pM, less than500 pM, less than 250 pM, less than 200 pM, less than 150 pM, less than100 pM, less than 75 pM, less than 10 pM, less than 1 pM as assessedusing a method described herein or known to one of skill in the art(e.g., a BIAcore assay, ELISA, FACS, SET) (Biacore International AB,Uppsala, Sweden).

The term “K_(assoc)” or “K_(a)”, as used herein, refers to theassociation rate of a particular antibody-antigen interaction, whereasthe term “K_(dis)” or “K_(d),” as used herein, refers to thedissociation rate of a particular antibody-antigen interaction. The term“K_(D)”, as used herein, refers to the dissociation constant, which isobtained from the ratio of K_(d) to K_(a) (i.e. K_(d)/K_(a)) and isexpressed as a molar concentration (M). K_(D) values for antibodies canbe determined using methods well established in the art. A method fordetermining the K_(D) of an antibody is by using surface plasmonresonance, or using a biosensor system such as a Biacore® system.

The term “affinity” as used herein refers to the strength of interactionbetween antibody and antigen at single antigenic sites. Within eachantigenic site, the variable region of the antibody “arm” interactsthrough weak non-covalent forces with antigen at numerous sites; themore interactions, the stronger the affinity.

The term “avidity” as used herein refers to an informative measure ofthe overall stability or strength of the antibody-antigen complex. It iscontrolled by three major factors: antibody epitope affinity; thevalence of both the antigen and antibody; and the structural arrangementof the interacting parts. Ultimately these factors define thespecificity of the antibody, that is, the likelihood that the particularantibody is binding to a precise antigen epitope.

The term “valency” as used herein refers to the number of potentialtarget binding sites in a polypeptide. Each target binding sitespecifically binds one target molecule or specific site (i.e, epitope)on a target molecule. When a polypeptide comprises more than one targetbinding site, each target binding site may specifically bind the same ordifferent molecules (e.g., may bind to different molecules, e.g.,different antigens, or different epitopes on the same molecule).

The phrase “inhibiting antibody” as used herein refers to an antibodythat binds with HER3 and inhibits the biological activity of HER3signaling, e.g., reduces, decreases and/or inhibits HER3 inducedsignaling activity, e.g., in a phospho-HER3 or phospho-Akt assay.Examples of assays are described in more details in the examples below.Accordingly, an antibody that “inhibits” one or more of these HER3functional properties (e.g., biochemical, immunochemical, cellular,physiological or other biological activities, or the like) as determinedaccording to methodologies known to the art and described herein, willbe understood to relate to a statistically significant decrease in theparticular activity relative to that seen in the absence of the antibody(e.g., or when a control antibody of irrelevant specificity is present).An antibody that inhibits HER3 activity effects such a statisticallysignificant decrease by at least 10% of the measured parameter, by atleast 50%, 80% or 90%, and in certain embodiments an antibody of theinvention may inhibit greater than 95%, 98% or 99% of HER3 functionalactivity as evidenced by a reduction in the level of cellular HER3phosphorylation.

The phrase “isolated antibody” refers to an antibody that issubstantially free of other antibodies having different antigenicspecificities (e.g., an isolated antibody that specifically binds HER3is substantially free of antibodies that specifically bind antigensother than HER3). An isolated antibody that specifically binds HER3 may,however, have cross-reactivity to other antigens. Moreover, an isolatedantibody may be substantially free of other cellular material and/orchemicals.

The phrase “conservatively modified variant” applies to both amino acidand nucleic acid sequences. With respect to particular nucleic acidsequences, conservatively modified variants refers to those nucleicacids which encode identical or essentially identical amino acidsequences, or where the nucleic acid does not encode an amino acidsequence, to essentially identical sequences. Because of the degeneracyof the genetic code, a large number of functionally identical nucleicacids encode any given protein. For instance, the codons GCA, GCC, GCGand GCU all encode the amino acid alanine. Thus, at every position wherean alanine is specified by a codon, the codon can be altered to any ofthe corresponding codons described without altering the encodedpolypeptide. Such nucleic acid variations are “silent variations,” whichare one species of conservatively modified variations. Every nucleicacid sequence herein which encodes a polypeptide also describes everypossible silent variation of the nucleic acid. One of skill willrecognize that each codon in a nucleic acid (except AUG, which isordinarily the only codon for methionine, and TGG, which is ordinarilythe only codon for tryptophan) can be modified to yield a functionallyidentical molecule. Accordingly, each silent variation of a nucleic acidthat encodes a polypeptide is implicit in each described sequence.

For polypeptide sequences, “conservatively modified variants” includeindividual substitutions, deletions or additions to a polypeptidesequence which result in the substitution of an amino acid with achemically similar amino acid. Conservative substitution tablesproviding functionally similar amino acids are well known in the art.Such conservatively modified variants are in addition to and do notexclude polymorphic variants, interspecies homologs, and alleles of theinvention. The following eight groups contain amino acids that areconservative substitutions for one another: 1) Alanine (A), Glycine (G);2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine(Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L),Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y),Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C),Methionine (M) (see, e.g., Creighton, Proteins (1984)). In someembodiments, the term “conservative sequence modifications” are used torefer to amino acid modifications that do not significantly affect oralter the binding characteristics of the antibody containing the aminoacid sequence.

The terms “cross-compete” and “cross-competing” are used interchangeablyherein to mean the ability of an antibody or fragment thereof tointerfere with the binding of other antibodies or fragments thereof toHER3 in a standard competitive binding assay.

The ability or extent to which an antibody of fragment thereof is ableto interfere with the binding of another antibody or fragment thereof toHER3, and therefore whether it can be said to cross-compete according tothe invention, can be determined using standard competition bindingassays. One suitable assay involves the use of the Biacore technology(e.g. by using the BIAcore 3000 instrument (Biacore, Uppsala, Sweden)),which can measure the extent of interactions using surface plasmonresonance technology. Another assay for measuring cross-competing usesan ELISA-based approach.

The term “optimized” as used herein refers to a nucleotide sequence hasbeen altered to encode an amino acid sequence using codons that arepreferred in the production cell or organism, generally a eukaryoticcell, for example, a cell of Pichia, a cell of Trichoderma, a ChineseHamster Ovary cell (CHO) or a human cell. The optimized nucleotidesequence is engineered to retain completely or as much as possible theamino acid sequence originally encoded by the starting nucleotidesequence, which is also known as the “parental” sequence.

Standard assays to evaluate the binding ability of the antibodies towardHER3 of various species are known in the art, including for example,ELISAs, western blots and RIAs. Suitable assays are described in detailin the Examples. The binding kinetics (e.g., binding affinity) of theantibodies also can be assessed by standard assays known in the art,such as by Biacore analysis, or FACS relative affinity (Scatchard).Assays to evaluate the effects of the antibodies on functionalproperties of HER3 (e.g., receptor binding assays, modulating the HER3signal pathway) are described in further detail in the Examples.

The phrases “percent identical” or “percent identity,” in the context oftwo or more nucleic acids or polypeptide sequences, refers to two ormore sequences or subsequences that are the same. Two sequences are“substantially identical” if two sequences have a specified percentageof amino acid residues or nucleotides that are the same (i.e., 60%identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identityover a specified region, or, when not specified, over the entiresequence), when compared and aligned for maximum correspondence over acomparison window, or designated region as measured using one of thefollowing sequence comparison algorithms or by manual alignment andvisual inspection. Optionally, the identity exists over a region that isat least about 50 nucleotides (or 10 amino acids) in length, or morepreferably over a region that is 100 to 500 or 1000 or more nucleotides(or 20, 50, 200 or more amino acids) in length.

For sequence comparison, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Default programparameters can be used, or alternative parameters can be designated. Thesequence comparison algorithm then calculates the percent sequenceidentities for the test sequences relative to the reference sequence,based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 20 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith and Waterman, (1970) Adv. Appl. Math. 2:482c, by the homologyalignment algorithm of Needleman and Wunsch, (1970) J. Mol. Biol.48:443, by the search for similarity method of Pearson and Lipman,(1988) Proc. Nat'l. Acad. Sci. USA 85:2444, by computerizedimplementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA inthe Wisconsin Genetics Software Package, Genetics Computer Group, 575Science Dr., Madison, Wis.), or by manual alignment and visualinspection (see, e.g., Brent et al., (2003) Current Protocols inMolecular Biology).

Two examples of algorithms that are suitable for determining percentsequence identity and sequence similarity are the BLAST and BLAST 2.0algorithms, which are described in Altschul et al., (1977) Nuc. AcidsRes. 25:3389-3402; and Altschul et al., (1990) J. Mol. Biol.215:403-410, respectively. Software for performing BLAST analyses ispublicly available through the National Center for BiotechnologyInformation. This algorithm involves first identifying high scoringsequence pairs (HSPs) by identifying short words of length W in thequery sequence, which either match or satisfy some positive-valuedthreshold score T when aligned with a word of the same length in adatabase sequence. T is referred to as the neighborhood word scorethreshold (Altschul et al., supra). These initial neighborhood word hitsact as seeds for initiating searches to find longer HSPs containingthem. The word hits are extended in both directions along each sequencefor as far as the cumulative alignment score can be increased.Cumulative scores are calculated using, for nucleotide sequences, theparameters M (reward score for a pair of matching residues; always >0)and N (penalty score for mismatching residues; always <0). For aminoacid sequences, a scoring matrix is used to calculate the cumulativescore. Extension of the word hits in each direction are halted when: thecumulative alignment score falls off by the quantity X from its maximumachieved value; the cumulative score goes to zero or below, due to theaccumulation of one or more negative-scoring residue alignments; or theend of either sequence is reached. The BLAST algorithm parameters W, T,and X determine the sensitivity and speed of the alignment. The BLASTNprogram (for nucleotide sequences) uses as defaults a wordlength (W) of11, an expectation (E) or 10, M=5, N=−4 and a comparison of bothstrands. For amino acid sequences, the BLASTP program uses as defaults awordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoringmatrix (see Henikoff and Henikoff, (1989) Proc. Natl. Acad. Sci. USA89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and acomparison of both strands.

The BLAST algorithm also performs a statistical analysis of thesimilarity between two sequences (see, e.g., Karlin and Altschul, (1993)Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarityprovided by the BLAST algorithm is the smallest sum probability (P(N)),which provides an indication of the probability by which a match betweentwo nucleotide or amino acid sequences would occur by chance. Forexample, a nucleic acid is considered similar to a reference sequence ifthe smallest sum probability in a comparison of the test nucleic acid tothe reference nucleic acid is less than about 0.2, more preferably lessthan about 0.01, and most preferably less than about 0.001.

The percent identity between two amino acid sequences can also bedetermined using the algorithm of E. Meyers and W. Miller, (1988)Comput. Appl. Biosci. 4:11-17) which has been incorporated into theALIGN program (version 2.0), using a PAM120 weight residue table, a gaplength penalty of 12 and a gap penalty of 4. In addition, the percentidentity between two amino acid sequences can be determined using theNeedleman and Wunsch (1970) J. Mol. Biol. 48:444-453) algorithm whichhas been incorporated into the GAP program in the GCG software package(available at www.gcg.com), using either a Blossom 62 matrix or a PAM250matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a lengthweight of 1, 2, 3, 4, 5, or 6.

Other than percentage of sequence identity noted above, anotherindication that two nucleic acid sequences or polypeptides aresubstantially identical is that the polypeptide encoded by the firstnucleic acid is immunologically cross reactive with the antibodiesraised against the polypeptide encoded by the second nucleic acid, asdescribed below. Thus, a polypeptide is typically substantiallyidentical to a second polypeptide, for example, where the two peptidesdiffer only by conservative substitutions. Another indication that twonucleic acid sequences are substantially identical is that the twomolecules or their complements hybridize to each other under stringentconditions, as described below. Yet another indication that two nucleicacid sequences are substantially identical is that the same primers canbe used to amplify the sequence.

The phrase “nucleic acid” is used herein interchangeably with the term“polynucleotide” and refers to deoxyribonucleotides or ribonucleotidesand polymers thereof in either single- or double-stranded form. The termencompasses nucleic acids containing known nucleotide analogs ormodified backbone residues or linkages, which are synthetic, naturallyoccurring, and non-naturally occurring, which have similar bindingproperties as the reference nucleic acid, and which are metabolized in amanner similar to the reference nucleotides. Examples of such analogsinclude, without limitation, phosphorothioates, phosphoramidates, methylphosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides,peptide-nucleic acids (PNAs).

Unless otherwise indicated, a particular nucleic acid sequence alsoimplicitly encompasses conservatively modified variants thereof (e.g.,degenerate codon substitutions) and complementary sequences, as well asthe sequence explicitly indicated. Specifically, as detailed below,degenerate codon substitutions may be achieved by generating sequencesin which the third position of one or more selected (or all) codons issubstituted with mixed-base and/or deoxyinosine residues (Batzer et al.,(1991) Nucleic Acid Res. 19:5081; Ohtsuka et al., (1985) J. Biol. Chem.260:2605-2608; and Rossolini et al., (1994) Mol. Cell. Probes 8:91-98).

The phrase “operably linked” refers to a functional relationship betweentwo or more polynucleotide (e.g., DNA) segments. Typically, it refers tothe functional relationship of a transcriptional regulatory sequence toa transcribed sequence. For example, a promoter or enhancer sequence isoperably linked to a coding sequence if it stimulates or modulates thetranscription of the coding sequence in an appropriate host cell orother expression system. Generally, promoter transcriptional regulatorysequences that are operably linked to a transcribed sequence arephysically contiguous to the transcribed sequence, i.e., they arecis-acting. However, some transcriptional regulatory sequences, such asenhancers, need not be physically contiguous or located in closeproximity to the coding sequences whose transcription they enhance.

The terms “polypeptide” and “protein” are used interchangeably herein torefer to a polymer of amino acid residues. The terms apply to amino acidpolymers in which one or more amino acid residue is an artificialchemical mimetic of a corresponding naturally occurring amino acid, aswell as to naturally occurring amino acid polymers and non-naturallyoccurring amino acid polymer. Unless otherwise indicated, a particularpolypeptide sequence also implicitly encompasses conservatively modifiedvariants thereof.

The term “subject” as used herein includes human and non-human animals.Non-human animals include all vertebrates, e.g., mammals andnon-mammals, such as non-human primates, sheep, dog, cow, chickens,amphibians, and reptiles. Except when noted, the terms “patient” or“subject” are used herein interchangeably.

The term “anti-cancer agent” as used herein refers to any agent that canbe used to treat a cell proliferative disorder such as cancer, includingcytotoxic agents, chemotherapeutic agents, radiotherapy andradiotherapeutic agents, targeted anti-cancer agents, andimmunotherapeutic agents.

The term “tumor” as used herein refers to neoplastic cell growth andproliferation, whether malignant or benign, and all pre-cancerous andcancerous cells and tissues.

The term “anti-tumor activity” as used herein refers to a reduction inthe rate of tumor cell proliferation, viability, or metastatic activity.A possible way of showing anti-tumor activity is show a decline ingrowth rate of abnormal cells that arises during therapy or tumor sizestability or reduction. Such activity can be assessed using accepted invitro or in vivo tumor models, including but not limited to xenograftmodels, allograft models, MMTV models, and other known models known inthe art to investigate anti-tumor activity.

The term “malignancy” as used herein refers to a non-benign tumor or acancer.

The term “cancer” as used herein refers to a malignancy characterized byderegulated or uncontrolled cell growth. Exemplary cancers include:carcinomas, sarcomas, leukemias, and lymphomas. The term “cancer”includes primary malignant tumors (e.g., those whose cells have notmigrated to sites in the subject's body other than the site of theoriginal tumor) and secondary malignant tumors (e.g., those arising frommetastasis, the migration of tumor cells to secondary sites that aredifferent from the site of the original tumor).

Various aspects of the invention are described in further detail in thefollowing sections and subsections.

Structure and Mechanism of Activation of the HER Receptors

All four HER receptors have an extracellular ligand-binding domain, asingle trans-membrane domain and a cytoplasmic tyrosinekinase-containing domain. The intracellular tyrosine kinase domain ofHER receptors is highly conserved, although the kinase domain of HER3contains substitutions of critical amino acids and therefore lackskinase activity (Guy et al., (1994): PNAS 91, 8132-8136). Ligand-induceddimerisation of the HER receptors induces activation of the kinase,receptor transphosphorylation on tyrosine residues in the C-terminaltail, followed by recruitment and activation of intracellular signallingeffectors (Yarden and Sliwkowski, (2001) Nature Rev 2, 127-137; Jorissenet al., (2003) Exp Cell Res 284, 31-53.

The crystal structures of the extracellular domains of HERs haveprovided some insight into the process of ligand-induced receptoractivation (Schlessinger, (2002) Cell 110, 669-672). The extracellulardomain of each HER receptor consists of four subdomains: Subdomain I andIII cooperate in forming the ligand-binding site, whereas subdomain II(and perhaps also subdomain IV) participates in receptor dimerisationvia direct receptor-receptor interactions. In the structures ofligand-bound HER1, a β hairpin (termed the dimerisation loop) insubdomain II interacts with the dimerisation loop of the partnerreceptor, mediating receptor dimerisation (Garrett et al, (2002) Cell110, 763-773; Ogiso et al., (2002) Cell 110, 775-787). In contrast, inthe structures of the inactive HER1, HER3 and HER4, the dimerisationloop is engaged in intramolecular interactions with subdomain IV, whichprevents receptor dimerisation in the absence of ligand (Cho and Leahy,(2002) Science 297, 1330-1333; Ferguson et al., (2003) Mol Cell 12,541-552; Bouyan et al., (2005) PNAS 102, 15024-15029). The structure ofHER2 is unique among the HERs. In the absence of a ligand, HER2 has aconformation that resembles the ligand-activated state of HER1 with aprotruding dimerisation loop, available to interact with other HERreceptors (Cho et al., (2003) Nature 421, 756-760; Garrett et al.,(2003) Mol Cell 11, 495-505). This may explain the enhancedheterodimerisation capacity of HER2.

Although the HER receptor crystal structures provide a model for HERreceptor homo- and heterodimerisation, the background for the prevalenceof some HER homo- and heterodimers over others (Franklin et al., (2004)Cancer Cell 5, 317-328) as well as the role of each of the domain inreceptor dimerisation and autoinhibition (Burgess et al., (2003) MolCell 12, 541-552; Mattoon et al., (2004) PNAS 101, 923-928) remainssomewhat unclear.

HER3 Structure and Epitopes

A conformational epitope to which anti-HER3 antibodies bind, haspreviously been described in PCT/EP2011/064407, and U.S. Ser. No.61/375,408, both filed Aug. 22, 2011, and which are incorporated hereinby reference in their entirety. The three dimensional structure of atruncated form of HER3 complexed with a HER3 antibody fragment, showedconformational epitope comprising domain 2 and domain 4 of HER3.

The present invention provides an additional class of antibodies orfragments thereof that bind a non-linear epitope within domain 3 ofHER3. These antibodies or fragments thereof bind with HER3 to inhibitboth ligand dependent and ligand independent signal transduction.

The present invention further provides a class of antibodies orfragments thereof that bind within domains 3-4 of HER3 to inhibit bothligand dependent and ligand independent signal transduction. In oneembodiment, the class of antibodies or fragments thereof binds to domain3 or domain 4 of HER3 to inhibit both ligand dependent and ligandindependent signal transduction. In another embodiment, the class ofantibodies or fragments thereof binds to domain 3 and domain 4 of HER3to inhibit both ligand dependent and ligand independent signaltransduction.

The present Examples present the crystal structure of HER3 bound to theFab fragment of MOR12604 determined at 3.38 Å resolution.

The three dimensional structure of a truncated form (residues 20-640) ofthe extracellular domain of HER3 complexed with an antibody have beenshown. The HER3-MOR12604 Fab complex was determined at 3.38 Åresolution, and shown in FIG. 4.

Although not bound to provide a theory, one possible model for themechanism of action is that HER3 typically exists in an inactive(closed, tethered) or active (open) state. Ligand binding induces aconformational change such that HER3 exists in the active (open) statewhich is capable of binding heterodimer partners resulting in activationin downstream signaling. Antibodies such as MOR12604 bind the inactive(tethered) state of HER3 and apparently block the ligand binding site.

Binding within domain 3 by MOR12604 suggests that MOR12604 couldfunction by a mechanisms selected from the group consisting of blockingHER3 residues required for ligand binding, preventing HER3 adopting theactive conformation due to steric hindrance between the antibody anddomains of HER3, preventing HER3 adopting the active conformation byreducing the degree of flexibility in HER3 hinge regions (e.g. domain3), inducing a conformational change in domain 3 loop 371-377 thatprevents HER3 from transitioning to the open conformation, destabilizingHER3 such that it is prone to degradation, acting as a partial agonistto accelerate the down regulation of HER3, and by each arm of MOR12604binding a molecule of HER3 such that the antibody generates anun-natural HER3 dimer that is either prone to proteolytic degradation orcannot dimerize with other receptor tyrosine kinases

To examine the crystal structure of domain 3 antibodies or fragmentsthereof bound to HER3, crystals of HER3 were prepared by expressing anucleotide sequence encoding HER3 or a variant thereof in a suitablehost cell, and then crystallising the purified protein(s) in thepresence of the relevant HER3 targeted Fab. Preferably the HER3polypeptide contains the extracellular domain (amino acids 20 to 640 ofthe human polypeptide (SEQ ID NO: 1) or a truncated version thereof,preferably comprising amino acids 20-640) but lacks the transmembraneand intracellular domains.

HER3 polypeptides may also be produced as fusion proteins, for exampleto aid in extraction and purification. Examples of fusion proteinpartners include glutathione-5-transferase (GST), histidine (HIS),hexahistidine (6HIS) (SEQ ID NO: 702), GAL4 (DNA binding and/ortranscriptional activation domains) and beta-galactosidase. It may alsobe convenient to include a proteolytic cleavage site between the fusionprotein partner and the protein sequence of interest to allow removal offusion protein sequences.

After expression, the proteins may be purified and/or concentrated, forexample by immobilised metal affinity chromatography, ion-exchangechromatography, and/or gel filtration.

The protein(s) may be crystallised using techniques described herein.Commonly, in a crystallisation process, a drop containing the proteinsolution is mixed with the crystallisation buffer and allowed toequilibrate in a sealed container. Equilibration may be achieved byknown techniques such as the “hanging drop” or the “sitting drop”method. In these methods, the drop is hung above or sitting beside amuch larger reservoir of crystallization buffer and equilibration isreached through vapor diffusion. Alternatively, equilibration may occurby other methods, for example under oil, through a semi-permeablemembrane, or by free-interface diffusion (See e.g., Chayen et al.,(2008) Nature Methods 5, 147-153.

Once the crystals have been obtained, the structure may be solved byknown X-ray diffraction techniques. Many techniques use chemicallymodified crystals, such as those modified by heavy atom derivatizationto approximate phases. In practice, a crystal is soaked in a solutioncontaining heavy metal atom salts, or organometallic compounds, e.g.,lead chloride, gold thiomalate, thimerosal or uranyl acetate, which candiffuse through the crystal and bind to the surface of the protein. Thelocation(s) of the bound heavy metal atom(s) can then be determined byX-ray diffraction analysis of the soaked crystal. The patterns obtainedon diffraction of a monochromatic beam of X-rays by the atoms(scattering centres) of the crystal can be solved by mathematicalequations to give mathematical coordinates. The diffraction data areused to calculate an electron density map of the repeating unit of thecrystal. Another method of obtaining phase information is using atechnique known as molecular replacement.

In this method, rotational and translational algorithms are applied to asearch model derived from a related structure, resulting in anapproximate orientation for the protein of interest (See Rossmann,(1990) Acta Crystals A 46, 73-82). The electron density maps are used toestablish the positions of the individual atoms within the unit cell ofthe crystal (Blundel et al., (1976) Protein Crystallography, AcademicPress).

The present disclosure describes the three-dimensional structure of HER3and a Fab of an anti-HER3 antibody. The approximate domain boundaries ofextracellular domain of HER3 are as follows; domain 1: amino acids20-207; domain 2: amino acids 208-328; domain 3: amino acids 329-498;and domain 4: amino acids 499-642. The three-dimensional structure ofHER3 and the antibody allows the identification of target binding sitesfor potential HER3 modulators. Preferred target binding sites are thoseinvolved in the activation of HER3. In one embodiment, the targetbinding site is located within domain 3 of HER3. Thus an antibody orfragment thereof which binds to domain 3 can, for example, modulate HER3activation by modifying the relative position of the domain relative toitself or other HER3 domains. Thus binding an antibody or fragmentthereof to amino acid residues within domain 3 may cause the protein toadopt a configuration that prevents activation.

In some embodiments, the antibody or fragment thereof binds to a bindingsurface of HER3. This binding surface comprises multiple contiguous ornon-contiguous surfaces in a 3D configuration that form part of theepitope which interacts with the antibody or fragment thereof. Forexample, a binding surface can comprise at least two surfaces (e.g.,surface A and surface B, see FIG. 4D), at least three surfaces (e.g.,surface A, surface B, and surface C), at least four surfaces (e.g.,surface A, surface B, surface C, and surface D), at least five surfaces(e.g., surface A, surface B, surface C, surface D, and surface E), atleast six surfaces (e.g., surface A, surface B, surface C, surface D,surface E, and surface F), at least seven surfaces (e.g., surface A,surface B, surface C, surface D, surface E, surface F, and surface G),at least eight surfaces (e.g., surface A, surface B, surface C, surfaceD, surface E, surface F, surface G, and surface H), at least ninesurfaces (e.g., surface A, surface B, surface C, surface D, surface E,surface F, surface G, surface H, and surface I), or at least tensurfaces (e.g., surface A, surface B, surface C, surface D, surface E,surface F, surface G, surface H, surface I, and surface J).

In one embodiment, the antibody or fragment thereof binds to bindingsurface A. In one embodiment, the antibody or fragment thereof binds tobinding surface B. In another embodiment, the antibody or fragmentthereof binds to both binding surface A and binding surface B. In oneembodiment, binding surface A comprises at least one amino acid residueselected from amino acid residues 362-376. In one embodiment, bindingsurface B comprises at least one amino acid residue selected from aminoacid residues 335-342, 398, 400, 424-428, 431, 433-434 and 455. Inanother embodiment, the antibody or fragment thereof binds to bindingsurface A, wherein at least one amino acid residue is selected fromamino acid residues 362-376; and binding surface B, wherein at least oneamino acid residue is selected from amino acid residues 335-342, 398,400, 424-428, 431, 433-434 and 455.

In some embodiments, the antibody or fragment thereof binds to humanHER3 protein having a non-linear epitope comprising HER3 amino acidresidues 335-342, 362-376, 398, 400, 424-428, 431, 433-434 and 455(within domain 3), of SEQ ID NO: 1, or a subset thereof. In someembodiments, the antibody or fragment thereof binds to amino acidswithin or overlapping amino acid residues 335-342, 362-376, 398, 400,424-428, 431, 433-434 and 455 (within domain 3), of SEQ ID NO: 1, or asubset thereof. In some embodiments, the antibody or fragment thereofbinds to amino acids within (and/or amino acid sequences consisting of)amino acids 335-342, 362-376, 398, 400, 424-428, 431, 433-434 and 455(within domain 3), of SEQ ID NO: 1, or a subset thereof.

In some embodiments, the antibody or fragment thereof binds to humanHER3 protein having an epitope (linear, non-linear, conformational)comprising HER3 amino acid residues 499-642 (of domain 4) of SEQ ID NO:1, or a subset thereof. In some embodiments, the antibody or fragmentthereof binds to amino acids within or overlapping amino acid residues499-642 (of domain 4) of SEQ ID NO: 1, or a subset thereof. In someembodiments, the antibody or fragment thereof binds to amino acidswithin (and/or amino acid sequences consisting of) amino acids residues499-642 (of domain 4) of SEQ ID NO: 1, or a subset thereof, or a subsetthereof.

In some embodiments, the antibody or fragment thereof binds to humanHER3 protein having a non-linear epitope comprising HER3 amino acidresidues 335-342, 362-376, 398,400,424-428, 431, 433-434 and 455 (withindomain 3) and an epitope (linear, non-linear, conformational) comprisingHER3 amino acid residues 499-642 (of domain 4) of SEQ ID NO: 1, or asubset thereof. In some embodiments, the antibody or fragment thereofbinds to amino acids within or overlapping amino acid residues 335-342,362-376, 398, 400, 424-428, 431, 433-434 and 455 (within domain 3), ofSEQ ID NO: 1 and an epitope (linear, non-linear, conformational)comprising HER3 amino acid residues 499-642 (of domain 4) of SEQ ID NO:1 or a subset thereof. In some embodiments, the antibody or fragmentthereof binds to amino acids within (and/or amino acid sequencesconsisting of) amino acids 335-342, 362-376, 398, 400, 424-428, 431,433-434 and 455 (within domain 3), and an epitope (linear, non-linear,conformational) comprising HER3 amino acid residues 499-642 (of domain4) of SEQ ID NO: 1 of SEQ ID NO: 1, or a subset thereof.

In some embodiments, the antibody or fragment thereof binds to humanHER3 protein having a epitope (linear, non-linear, conformational)comprising HER3 amino acid residues within domain 3 and an epitope(linear, non-linear, conformational) comprising HER3 amino acid residueswithin of domain 4 of SEQ ID NO: 1, or a subset thereof. In someembodiments, the antibody or fragment thereof binds to amino acidswithin or overlapping amino acid residues of domain 3 and amino acids ofdomain 4 of SEQ ID NO: 1, or a subset thereof.

In some embodiments, the antibody or fragment thereof binds to theinactive state of the HER3 receptor, thereby preventing HER3 adopting anactive conformation. In some embodiments, the antibody or fragmentthereof prevents HER3 adopting an active conformation due to sterichindrance between the antibody or fragment thereof and domains of HER3(e.g., with MOR12604, steric interference with domain 1 of HER3). Insome embodiments, the antibody or fragment thereof prevents HER3adopting an active conformation by reducing the degree of flexibility indomain 3. In some embodiments, the antibody or fragment thereof inducesa conformational change in domain 3 loop 371-377 of SEQ ID NO:1 thatprevents HER3 from adopting an active conformation. In some embodiments,the antibody or fragment thereof destabilizes HER3 such that it issusceptible to degradation. In some embodiments, the antibody orfragment thereof accelerates down regulation of cell surface HER3. Insome embodiments, the antibody or fragment thereof generates anun-natural HER3 dimer that is susceptible to proteolytic degradation orunable to dimerize with other receptor tyrosine kinases.

In some embodiments, the antibody or fragment thereof can bind to eitherthe active or inactive state of HER3. In some embodiments, the antibodyor fragment thereof stabilizes the HER3 receptor in an inactive statesuch that the HER3 receptor fails to dimerize with a co-receptor to forma receptor-receptor complex. The failure to form a receptor-receptorcomplex prevents activation of both ligand-dependent andligand-independent signal transduction.

In some embodiments, the antibody or fragment thereof inducesdimerization of HER3 with HER3 to form an inactive receptor-receptorcomplex. The formation of the inactive receptor-receptor complexprevents activation of HER3 mediated signal transduction since HER3 issequestered in inactive receptor-receptor complexes.

The depicted structure also allows one to identify specific HER3 aminoacid residues for the interaction interface of an antibody or fragmentthereof (e.g., MOR12604) with HER3. This was defined as residues thatare within 5 Å of the MOR12604 protein VH chain. The residues are asfollows: Ile365, Thr366, Asn369, Gly370, Asp371, Pro372, Trp373, His374,Lys375, Gln400, and Lys434. The depicted structure also allows one toidentify specific HER3 amino acid residues for the interaction interfaceof an antibody or fragment thereof (e.g., MOR12604) with HER3. This wasdefined as residues that are within 5 Å of the MOR12604 protein VLchain. The residues are as follows: Gly335, Ser336, Gly337, Ser338,Phe340, Gln341, Asp362, Leu364, Ile365, Thr366, His374, Ile376, Asn398,Gln400, Tyr424, Asn425, Arg426, Phe428, Leu431, Met433, Lys434, Tyr455.As can be seen in Tables 5 and 6 (MOR12604), respectively, both thelight and heavy chains are involved in the antigen binding protein'sbinding to amino acid residues within domain 3 of the epitope.

As such, one of skill in the art, given the present teachings, canpredict which residues and areas of the antigen binding proteins can bevaried without unduly interfering with the antigen binding protein'sability to bind to domains 3 and 4 of HER3.

Core interaction interface amino acids were determined as being allamino acid residues with at least one atom less than or equal to 5 Åfrom the HER3 partner protein. 5 Å was chosen as the core region cutoffdistance to allow for atoms within a van der Waals radius plus apossible water-mediated hydrogen bond.

In some embodiments, any antigen binding protein that binds to, covers,or prevents MOR12604 from interacting with any of the above residues canbe employed to bind to or neutralize HER3. In some embodiments, theantibodies or fragments thereof binds to or interacts with at least oneof the following HER3 residues (SEQ ID NO: 1): Ile365, Thr366, Asn369,Gly370, Asp371, Pro372, Trp373, His374, Lys375, Gln400, and Lys434. Insome embodiments, the antibodies and fragments thereof binds to orinteracts with at least one of the following HER3 residues (SEQ ID NO:1): Gly335, Ser336, Gly337, Ser338, Phe340, Gln341, Asp362, Leu364,Ile365, Thr366, His374, Ile376, Asn398, Gln400, Tyr424, Asn425, Arg426,Phe428, Leu431, Met433, Lys434, Tyr455. In some embodiments, theantibodies or fragments thereof binds to or interacts with at least oneof the following HER3 residues (SEQ ID NO: 1): Ile365, Thr366, Asn369,Gly370, Asp371, Pro372, Trp373, His374, Lys375, Gln400, Lys434, Gly335,Ser336, Gly337, Ser338, Phe340, Gln341, Asp362, Leu364, Ile365, Thr366,His374, Ile376, Asn398, Gln400, Tyr424, Asn425, Arg426, Phe428, Leu431,Met433, Lys434, Tyr455. In some embodiments, the antibodies or fragmentsthereof binds to or interacts with a combination of the following HER3residues (SEQ ID NO: 1): Ile365, Thr366, Asn369, Gly370, Asp371, Pro372,Trp373, His374, Lys375, Gln400, Lys434, Gly335, Ser336, Gly337, Ser338,Phe340, Gln341, Asp362, Leu364, Ile365, Thr366, His374, Ile376, Asn398,Gln400, Tyr424, Asn425, Arg426, Phe428, Leu431, Met433, Lys434, Tyr455.In some embodiments, the antibodies or fragments thereof binds to orinteracts with all of the following HER3 residues (SEQ ID NO: 1):Ile365, Thr366, Asn369, Gly370, Asp371, Pro372, Trp373, His374, Lys375,Gln400, Lys434, Gly335, Ser336, Gly337, Ser338, Phe340, Gln341, Asp362,Leu364, Ile365, Thr366, His374, Ile376, Asn398, Gln400, Tyr424, Asn425,Arg426, Phe428, Leu431, Met433, Lys434, Tyr455. In some embodiments, theantibody or fragment thereof is within 5 angstroms of one or more of theabove residues. In some embodiments, the antibody or fragment thereof is5 to 8 angstroms from one or more of the above residues. In someembodiments, the antibody or fragment thereof interacts, blocks, or iswithin 8 angstroms of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,20, 25, 28, 30, 35, 40, 45, or 50 of the above residues.

The availability of 3D structures for the HER3 and the complex of HER3:MOR12604, for example, provides the framework to explore other HER3antibodies in more detail. The 3D structure of HER3 allows the epitopesfor monoclonal antibodies to be mapped and their mode of actioninferred, since some inhibit, some stimulate and others have no effecton cell growth. The non-linearepitope for MOR12604 has been located tothe domain 3 of HER3. The availability of the 3D structures of thisreceptor will facilitate the determination of the precise mechanism ofaction of these inhibitory agents and the design of new approaches tointerfering with HER3 receptor function. In one embodiment, theantibodies of the invention bind to the same non-linear epitope asMOR12604.

In some embodiments, the non-linear epitope bound by any of theantibodies listed in Table 1 is especially useful. In certainembodiments, a HER3 non-linear epitope can be utilized to isolateantibodies of fragments thereof that bind to HER3. In certainembodiments, a HER3 non-linear epitope can be utilized to generateantibodies or fragments thereof which bind to HER3. In certainembodiments, a HER3 non-linear epitope can be utilized as an immunogento generate antibodies of fragments thereof that bind to the HER3non-linear epitope. In certain embodiments, a HER3 non-linear epitopecan be administered to an animal, and antibodies that bind to HER3 cansubsequently be obtained from the animal.

The present invention also provides a class of antibodies that bind toan epitope (linear, non-linear, or conformational) within domains 3-4 ofHER3. Examples of such antibodies or fragments thereof that bind withindomains 3-4 are shown in Table 2. The above methodology and the methodsdescribed in the Example section below, can be also used to generatedomain 3-4 antibodies or fragments thereof complexed to HER3.

In some embodiments, the domain(s)/region(s) containing residues thatare in contact with or are buried by an antibody can be identified bymutating specific residues in HER3 (e.g., a wild-type antigen) anddetermining whether antibody or fragment thereof can bind the mutated orvariant HER3 protein or measure changes of affinity from wild-type. Bymaking a number of individual mutations, residues that play a directrole in binding or that are in sufficiently close proximity to theantibody such that a mutation can affect binding between the antibodyand antigen can be identified. From a knowledge of these amino acids,the domain(s) or region(s) of the antigen (HER3) that contain residuesin contact with the antibody or covered by the antibody can beelucidated. Mutagenesis using known techniques such as alanine-scanningcan help define functionally relevant epitopes. Mutagenesis utilizing anarginine/glutamic acid scanning protocol can also be employed (see,e.g., Nanevicz et al., (1995), J. Biol. Chem. 270(37):21619-21625 andZupnick et al., (2006), J. Biol. Chem. 281(29):20464-20473). In general,arginine and glutamic acids are substituted (typically individually) foran amino acid in the wild-type polypeptide because these amino acids arecharged and bulky and thus have the potential to disrupt binding betweenan antigen binding protein and an antigen in the region of the antigenwhere the mutation is introduced. Arginines that exist in the wild-typeantigen are replaced with glutamic acid. A variety of such individualmutants can be obtained and the collected binding results analyzed todetermine what residues affect binding. A series of mutant HER3 antigenscan be created, with each mutant antigen having a single mutation.Binding of each mutant HER3 antigen with various HER3 antibodies orfragments thereof can be measured and compared to the ability of theselected an antibody or fragments thereof to bind wild-type HER3 (SEQ IDNO: 1).

An alteration (for example a reduction or increase) in binding betweenan antibody or fragment thereof and a mutant or variant HER3 as usedherein means that there is a change in binding affinity (e.g., asmeasured by known methods such as Biacore testing or the bead basedassay described below in the examples), EC₅₀, and/or a change (forexample a reduction) in the total binding capacity of the antigenbinding protein (for example, as evidenced by a decrease in B_(max) in aplot of antigen binding protein concentration versus antigenconcentration). A significant alteration in binding indicates that themutated residue is involved in binding to the antibody or fragmentthereof.

In some embodiments, a significant reduction in binding means that thebinding affinity, EC₅₀, and/or capacity between an antibody or fragmentsthereof and a mutant HER3 antigen is reduced by greater than 10%,greater than 20%, greater than 40%, greater than 50%, greater than 55%,greater than 60%, greater than 65%, greater than 70%, greater than 75%,greater than 80%, greater than 85%, greater than 90% or greater than 95%relative to binding between the an antibody or fragment thereof and awild type HER3 (e.g., SEQ ID NO: 1).

In some embodiments, binding of an antibody or fragments thereof issignificantly reduced or increased for a mutant HER3 protein having oneor more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) mutations ascompared to a wild-type HER3 protein (e.g., SEQ ID NO: 1).

Although the variant forms are referenced with respect to the wild-typesequence shown in SEQ ID NO: 1, it will be appreciated that in anallelic or splice variants of HER3 the amino acids could differ.Antibodies or fragments thereof showing significantly altered binding(e.g., lower or higher binding) for such allelic forms of HER3 are alsocontemplated.

In addition to the general structural aspects of antibodies, the morespecific interaction between the paratope and the epitope may beexamined through structural approaches. In one embodiment, the structureof the CDRs contribute to a paratope, through which an antibody is ableto bind to an epitope. The shape of such a paratope may be determined ina number of ways. Traditional structural examination approaches can beused, such as NMR or x-ray crystallography. These approaches can examinethe shape of the paratope alone, or while it is bound to the epitope.Alternatively, molecular models may be generated in silico. A structurecan be generated through homology modeling, aided with a commercialpackage, such as InsightII modeling package from Accelrys (San Diego,Calif.). Briefly, one can use the sequence of the antibody to beexamined to search against a database of proteins of known structures,such as the Protein Data Bank. After one identifies homologous proteinswith known structures, these homologous proteins are used as modelingtemplates. Each of the possible templates can be aligned, thus producingstructure based sequence alignments among the templates. The sequence ofthe antibody with the unknown structure can then be aligned with thesetemplates to generate a molecular model for the antibody with theunknown structure. As will be appreciated by one of skill in the art,there are many alternative methods for generating such structures insilico, any of which may be used. For instance, a process similar to theone described in Hardman et al., issued U.S. Pat. No. 5,958,708employing QUANTA (Polygen Corp., Waltham, Mass.) and CHARM (Brooks etal., (1983), J. Comp. Chem. 4:187) may be used (hereby incorporated inits entirety by reference).

Not only is the shape of the paratope important in determining whetherand how well a possible paratope will bind to an epitope, but theinteraction itself, between the epitope and the paratope is a source ofgreat information in the design of variant antibodies. As appreciated byone of skill in the art, there are a variety of ways in which thisinteraction can be studied. One way is to use the structural modelgenerated, perhaps as described above, and then to use a program such asInsightII (Accelrys, San Diego, Calif.), which has a docking module,which, among other things, is capable of performing a Monte Carlo searchon the conformational and orientational spaces between the paratope andits epitope. The result is that one is able to estimate where and howthe epitope interacts with the paratope. In one embodiment, only afragment, or variant, of the epitope is used to assist in determiningthe relevant interactions. In one embodiment, the entire epitope is usedin the modeling of the interaction between the paratope and the epitope.

Through the use of these modelled structures, one is able to predictwhich residues are the most important in the interaction between theepitope and the paratope. Thus, in one embodiment, one is able toreadily select which residues to change in order to alter the bindingcharacteristics of the antibody. For instance, it may be apparent fromthe docking models that the side chains of certain residues in theparatope may sterically hinder the binding of the epitope, thus alteringthese residues to residues with smaller side chains may be beneficial.One can determine this in many ways. For example, one may simply look atthe two models and estimate interactions based on functional groups andproximity. Alternatively, one may perform repeated pairings of epitopeand paratope, as described above, in order to obtain more favorableenergy interactions. One can also determine these interactions for avariety of variants of the antibody to determine alternative ways inwhich the antibody may bind to the epitope. One can also combine thevarious models to determine how one should alter the structure of theantibodies in order to obtain an antibody with the particularcharacteristics that are desired.

The models determined above can be tested through various techniques.For example, the interaction energy can determined with the programsdiscussed above in order to determine which of the variants to furtherexamine. Also, coulumbic and van der Waals interactions are used todetermine the interaction energies of the epitope and the variantparatopes. Also site directed mutagenesis is used to see if predictedchanges in antibody structure actually result in the desired changes inbinding characteristics. Alternatively, changes may be made to theepitope to verify that the models are correct or to determine generalbinding themes that may be occurring between the paratope and theepitope.

As will be appreciated by one of skill in the art, while these modelswill provide the guidance necessary to make the antibodies and variantsthereof of the present embodiments, it may still be desirable to performroutine testing of the in silico models, perhaps through in vitrostudies. In addition, as will be apparent to one of skill in the art,any modification may also have additional side effects on the activityof the antibody. For instance, while any alteration predicted to resultin greater binding, may induce greater binding, it may also cause otherstructural changes which might reduce or alter the activity of theantibody. The determination of whether or not this is the case isroutine in the art and can be achieved in many ways. For example, theactivity can be tested through an ELISA test. Alternatively, the samplescan be tested through the use of a surface plasmon resonance device.

HER3 Antibodies

The present invention provides a class of antibodies that recognize anon-linear epitope within domain 3 of HER3 and inhibit bothligand-dependent and ligand-independent HER3 signal transductionpathways as shown in Table 1. The present invention also provides aclass of antibodies that recognize an epitope (linear, non-linear,conformational) within domains 3-4 of HER3 that inhibit bothligand-dependent and ligand-independent HER3 signal transductionpathways, as shown in Table 2

TABLE 1 Examples of HER3 antibodies that bind to a non-linear epitopewithin domain 3 of HER3. MOR09627 SEQ ID NO: 2 (Kabat) HCDR1 SYAIS SEQID NO: 3 (Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 4 (Kabat) HCDR3NWPYYYMDF SEQ ID NO: 5 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 6 (Chothia)HCDR2 IPRYGK SEQ ID NO: 7 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 8 (Kabat)LCDR1 RASQNIVFNLA SEQ ID NO: 9 (Kabat) LCDR2 DASNRAT SEQ ID NO: 10(Kabat) LCDR3 QQHGSGPTT SEQ ID NO: 11 (Chothia) LCDR1 SQNIVFN SEQ ID NO:12 (Chothia) LCDR2 DAS SEQ ID NO: 13 (Chothia) LCDR3 HGSGPT SEQ ID NO:14 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 15 VLDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQHGSGPTTFGQGTKVEIK SEQ ID NO: 16 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 17 DNA VLGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTTTATTATTGCCAGCAGCATGGTTCTGGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA SEQ IDNO: 18 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:19 Light ChainDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQHGSGPTTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 20 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 21 DNA LightGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTTTATTATTGCCAGCAGCATGGTTCTGGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCG AGTGTMOR12603 SEQ ID NO: 22 (Kabat) HCDR1 SYAIS SEQ ID NO: 23 (Kabat) HCDR2LIIPRYGKARYAQKFQG SEQ ID NO: 24 (Kabat) HCDR3 NWPYYYMDF SEQ ID NO: 25(Chothia) HCDR1 GGTFSSY SEQ ID NO: 26 (Chothia) HCDR2 IPRYGK SEQ ID NO:27 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 28 (Kabat) LCDR1 RASQNIVFNLA SEQID NO: 29 (Kabat) LCDR2 DASNRAT SEQ ID NO: 30 (Kabat) LCDR3 QQTKNRPPTSEQ ID NO: 31 (Chothia) LCDR1 SQNIVFN SEQ ID NO: 32 (Chothia) LCDR2 DASSEQ ID NO: 33 (Chothia) LCDR3 TKNRPP SEQ ID NO: 34 VHQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 35 VLDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIK SEQ ID NO: 36 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 37 DNA VLGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA SEQ IDNO: 38 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 39 Light ChainDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 40 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 41 DNA LightGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG CGAGTGTMOR12604 SEQ ID NO: 42 (Kabat) HCDR1 SYAIS SEQ ID NO: 43 (Kabat) HCDR2LIIPRYGKARYAQKFQG SEQ ID NO: 44 (Kabat) HCDR3 NWPYYYMDF SEQ ID NO: 45(Chothia) HCDR1 GGTFSSY SEQ ID NO: 46 (Chothia) HCDR2 IPRYGK SEQ ID NO:47 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 48 (Kabat) LCDR1 RASQNIVFNLA SEQID NO: 49 (Kabat) LCDR2 DASNRAT SEQ ID NO: 50 (Kabat) LCDR3 QQKKSMPLTSEQ ID NO: 51 (Chothia) LCDR1 SQNIVFN SEQ ID NO: 52 (Chothia) LCDR2 DASSEQ ID NO: 53 (Chothia) LCDR3 KKSMPL SEQ ID NO: 54 VHQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 55 VLDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQKKSMPLTFGQGTKVEIK SEQ ID NO: 56 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 57 DNA VLGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGAAGAAGTCTATGCCTCTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA SEQ IDNO: 58 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 59 Light ChainDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQKKSMPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 60 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 61 DNA LightGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGAAGAAGTCTATGCCTCTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG CGAGTGTMOR12605 SEQ ID NO: 62 (Kabat) HCDR1 SYAIS SEQ ID NO: 63 (Kabat) HCDR2LIIPRYGKARYAQKFQG SEQ ID NO: 64 (Kabat) HCDR3 NWPYYYMDF SEQ ID NO: 65(Chothia) HCDR1 GGTFSSY SEQ ID NO: 66 (Chothia) HCDR2 IPRYGK SEQ ID NO:67 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 68 (Kabat) LCDR1 RASQNIVFNLA SEQID NO: 69 (Kabat) LCDR2 DASNRAT SEQ ID NO: 70 (Kabat) LCDR3 QQFRRKSNTSEQ ID NO: 71 (Chothia) LCDR1 SQNIVFN SEQ ID NO: 72 (Chothia) LCDR2 DASSEQ ID NO: 73 (Chothia) LCDR3 FRRKSN SEQ ID NO: 74 VHQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 75 VLDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQFRRKSNTFGQGTKVEIK SEQ ID NO: 76 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 77 DNA VLGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGTTTCGTCGTAAGTCTAATACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA SEQ IDNO: 78 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 79 Light ChainDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQFRRKSNTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 80 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 81 DNA LightGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGTTTCGTCGTAAGTCTAATACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGC GAGTGTMOR12606 SEQ ID NO: 82 (Kabat) HCDR1 SYAIS SEQ ID NO: 83 (Kabat) HCDR2LIIPRYGKARYAQKFQG SEQ ID NO: 84 (Kabat) HCDR3 NWPYYYMDF SEQ ID NO: 85(Chothia) HCDR1 GGTFSSY SEQ ID NO: 86 (Chothia) HCDR2 IPRYGK SEQ ID NO:87 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 88 (Kabat) LCDR1 RASQNIVFNLA SEQID NO: 89 (Kabat) LCDR2 DASNRAT SEQ ID NO: 90 (Kabat) LCDR3 QQTKSKPSPTSEQ ID NO: 91 (Chothia) LCDR1 SQNIVFN SEQ ID NO: 92 (Chothia) LCDR2 DASSEQ ID NO: 93 (Chothia) LCDR3 TKSKPSP SEQ ID NO: 94 VHQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 95 VLDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIK SEQ ID NO: 96 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 97 DNA VLGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATT AAASEQ ID NO: 98 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 99 Light ChainDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 100 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 101 DNA LightGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGT MOR12607 SEQ ID NO: 102 (Kabat) HCDR1 SYAIS SEQ ID NO: 103(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 104 (Kabat) HCDR3 NWPYYYMDFSEQ ID NO: 105 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 106 (Chothia) HCDR2IPRYGK SEQ ID NO: 107 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 108 (Kabat)LCDR1 RASQNIVFNLA SEQ ID NO: 109 (Kabat) LCDR2 DASNRAT SEQ ID NO: 110(Kabat) LCDR3 QQVKKRPFT SEQ ID NO: 111 (Chothia) LCDR1 SQNIVFN SEQ IDNO: 112 (Chothia) LCDR2 DAS SEQ ID NO: 113 (Chothia) LCDR3 VKKRPF SEQ IDNO: 114 VHQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 115 VLDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQVKKRPFTFGQGTKVEIK SEQ ID NO: 116 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 117 DNA VLGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGGTTAAGAAGCGTCCTTTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA SEQ IDNO: 118 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 119 Light ChainDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQVKKRPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 120 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 121 DNA LightGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGGTTAAGAAGCGTCCTTTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG CGAGTGTMOR12608 SEQ ID NO: 122 (Kabat) HCDR1 SYAIS SEQ ID NO: 123 (Kabat) HCDR2LIIPRYGKARYAQKFQG SEQ ID NO: 124 (Kabat) HCDR3 NWPYYYMDF SEQ ID NO: 125(Chothia) HCDR1 GGTFSSY SEQ ID NO: 126 (Chothia) HCDR2 IPRYGK SEQ ID NO:127 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 128 (Kabat) LCDR1 RASQNIVFNLASEQ ID NO: 129 (Kabat) LCDR2 DASNRAT SEQ ID NO: 130 (Kabat) LCDR3QQSYTRPTT SEQ ID NO: 131 (Chothia) LCDR1 SQNIVFN SEQ ID NO: 132(Chothia) LCDR2 DAS SEQ ID NO: 133 (Chothia) LCDR3 SYTRPT SEQ ID NO: 134VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 135 VLDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSYTRPTTFGQGTKVEIK SEQ ID NO: 136 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 137 DNA VLGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGTCTTATACTCGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA SEQ IDNO: 138 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 139 Light ChainDIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSYTRPTTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 140 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 141 DNA LightGATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGTCTTATACTCGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGC GAGTGTMOR14533 SEQ ID NO: 142 (Kabat) HCDR1 SYAIS SEQ ID NO: 143 (Kabat) HCDR2LIIPRYGKARYAQKFQG SEQ ID NO: 144 (Kabat) HCDR3 NWPYYYMDF SEQ ID NO: 145(Chothia) HCDR1 GGTFSSY SEQ ID NO: 146 (Chothia) HCDR2 IPRYGK SEQ ID NO:147 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 148 (Kabat) LCDR1 RASQNIVFNLASEQ ID NO: 149 (Kabat) LCDR2 DASNRAT SEQ ID NO: 150 (Kabat) LCDR3QQTKSKPSPT SEQ ID NO: 151 (Chothia) LCDR1 SQNIVFN SEQ ID NO: 152(Chothia) LCDR2 DAS SEQ ID NO: 153 (Chothia) LCDR3 TKSKPSP SEQ ID NO:154 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 155 VLEIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIK SEQ ID NO: 156 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 157 DNA VLGAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATT AAASEQ ID NO: 158 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 159 Light ChainEIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 160 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 161 DNA LightGAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGT MOR14534 SEQ ID NO: 162 (Kabat) HCDR1 SYAIS SEQ ID NO: 163(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 164 (Kabat) HCDR3 NWPYYYMDFSEQ ID NO: 165 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 166 (Chothia) HCDR2IPRYGK SEQ ID NO: 167 (Chothia) HCDR3 NWPYYYMDF SEQ ID NO: 168 (Kabat)LCDR1 RASQNIVFNLA SEQ ID NO: 169 (Kabat) LCDR2 DASNRAT SEQ ID NO: 170(Kabat) LCDR3 QQTKNRPPT SEQ ID NO: 171 (Chothia) LCDR1 SQNIVFN SEQ IDNO: 172 (Chothia) LCDR2 DAS SEQ ID NO: 173 (Chothia) LCDR3 TKNRPP SEQ IDNO: 174 VHQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 175 VLEIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIK SEQ ID NO: 176 DNA VHCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 177 DNA VLGAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTGAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA SEQ IDNO: 178 Heavy ChainQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 179 Light ChainEIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 180 DNA HeavyCAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG ChainCTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTTTCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATTTTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAASEQ ID NO: 181 DNA LightGAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG ChainAGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAGCACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGCTCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGTATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG CGAGTGT

TABLE 2 Examples of HER3 antibodies that bind to amino acids withindomains 3-4 of HER3. MOR12514 SEQ ID NO: 182 (Kabat) HCDR1 SYDIH SEQ IDNO: 183 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 184 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 185 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 186(Chothia) HCDR2 DPYSGN SEQ ID NO: 187 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 188 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 189 (Kabat) LCDR2GVSKRPS SEQ ID NO: 190 (Kabat) LCDR3 QVRDMSLFDV SEQ ID NO: 191 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 192 (Chothia) LCDR2 GVS SEQ ID NO: 193(Chothia) LCDR3 RDMSLFD SEQ ID NO: 194 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 195VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQVRDMSLFDVFGGGTKLTVL SEQ ID NO: 196 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 197 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGTTCGTGACATGTCTCTGTTCGACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 198 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:199 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQVRDMSLFDVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 200 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 201 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGTTCGTGACATGTCTCTGTTCGACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR12515 SEQ ID NO: 202 (Kabat) HCDR1 SYDIH SEQ ID NO:203 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 204 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 205 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 206(Chothia) HCDR2 DPYSGN SEQ ID NO: 207 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 208 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 209 (Kabat) LCDR2GVSKRPS SEQ ID NO: 210 (Kabat) LCDR3 YSRDSPMDQV SEQ ID NO: 211 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 212 (Chothia) LCDR2 GVS SEQ ID NO: 213(Chothia) LCDR3 RDSPMDQ SEQ ID NO: 214 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 215VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCYSRDSPMDQVFGGGTKLTVL SEQ ID NO: 216 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 217 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTACTCTCGTGACTCTCCGATGGACCAGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 218 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:219 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCYSRDSPMDQVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 220 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 221 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTACTCTCGTGACTCTCCGATGGACCAGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR12516 SEQ ID NO: 222 (Kabat) HCDR1 SYDIH SEQ ID NO:223 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 224 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 225 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 226(Chothia) HCDR2 DPYSGN SEQ ID NO: 227 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 228 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 229 (Kabat) LCDR2GVSKRPS SEQ ID NO: 230 (Kabat) LCDR3 QSRDTYRPVKV SEQ ID NO: 231(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 232 (Chothia) LCDR2 GVS SEQ ID NO:233 (Chothia) LCDR3 RDTYRPVK SEQ ID NO: 234 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 235VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSRDTYRPVKVFGGGTKLTVL SEQ ID NO: 236 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 237 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGTCTCGTGACACTTACCGTCCGGTTAAAGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 238 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 239 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSRDTYRPVKVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 240 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 241 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGTCTCGTGACACTTACCGTCCGGTTAAAGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR12615 SEQ ID NO: 242 (Kabat) HCDR1 SYDIH SEQ IDNO: 243 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 244 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 245 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 246(Chothia) HCDR2 DPYSGN SEQ ID NO: 247 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 248 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 249 (Kabat) LCDR2GVSKRPS SEQ ID NO: 250 (Kabat) LCDR3 SSRDLIGHYV SEQ ID NO: 251 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 252 (Chothia) LCDR2 GVS SEQ ID NO: 253(Chothia) LCDR3 RDLIGHY SEQ ID NO: 254 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 255VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 256 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 257 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 258 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 259 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 260 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 261 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR12920 SEQ ID NO: 262 (Kabat) HCDR1 GYYMH SEQ ID NO:263 (Kabat) HCDR2 DIEPYHGKPLYAQKFQG SEQ ID NO: 264 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 265 (Chothia) HCDR1 GYTFTGY SEQ ID NO: 266(Chothia) HCDR2 EPYHGK SEQ ID NO: 267 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 268 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 269 (Kabat) LCDR2GVSKRPS SEQ ID NO: 270 (Kabat) LCDR3 SSRDLIGHYV SEQ ID NO: 271 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 272 (Chothia) LCDR2 GVS SEQ ID NO: 273(Chothia) LCDR3 RDLIGHY SEQ ID NO: 274 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIEPYHGKPLYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO:275 VLDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGNAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 276 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAGCTGCAAAGGCTCCGGATATAGCTTCACTAACTCTTGGGTTGCTTGGGTGCGCCAGATGCCGGGCAAAGGTCTCGAGTGGATGGGCATCATCTACCCGGGTAACAGCGACACCATCTATAGCCCGAGCTTTCAGGGCCAGGTGACCATTAGCGCGGATAAAAGCATCAGCACCGCGTATCTGCAATGGAGCAGCCTGAAAGCGAGCGATACCGCGATGTATTATTGCGCGCGTGTTCATATCATCCAGCCGCCGTCTGCTTGGTCTTACAACGCTATGGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO:277 DNA VLGATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTGGGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGTCTATTTCTACTTACCTGAACTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAACTATTAATCTTCGGTGCTTCTAACCTGCAAAGCGGCGTGCCGAGCCGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATTAGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCCAGCAGTCTATCACTGAACTGTTCACCTTTGGCCAGGGCACGAAAGTTGAAATTAAA SEQ IDNO: 278 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIEPYHGKPLYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 279 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGNAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 280 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAG ChainCTGCAAAGGCTCCGGATATAGCTTCACTAACTCTTGGGTTGCTTGGGTGCGCCAGATGCCGGGCAAAGGTCTCGAGTGGATGGGCATCATCTACCCGGGTAACAGCGACACCATCTATAGCCCGAGCTTTCAGGGCCAGGTGACCATTAGCGCGGATAAAAGCATCAGCACCGCGTATCTGCAATGGAGCAGCCTGAAAGCGAGCGATACCGCGATGTATTATTGCGCGCGTGTTCATATCATCCAGCCGCCGTCTGCTTGGTCTTACAACGCTATGGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 281 DNA LightGATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTGGGCGATCGCGTGACCATT ChainACCTGCAGAGCCAGCCAGTCTATTTCTACTTACCTGAACTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAACTATTAATCTTCGGTGCTTCTAACCTGCAAAGCGGCGTGCCGAGCCGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATTAGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCCAGCAGTCTATCACTGAACTGTTCACCTTTGGCCAGGGCACGAAAGTTGAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGC GAGTGTMOR12921 SEQ ID NO: 282 (Kabat) HCDR1 GYYMH SEQ ID NO: 283 (Kabat) HCDR2DIDPHSGNAVYAQKFQG SEQ ID NO: 284 (Kabat) HCDR3 GSFYTRDSYFDV SEQ ID NO:285 (Chothia) HCDR1 GYTFTGY SEQ ID NO: 286 (Chothia) HCDR2 DPHSGN SEQ IDNO: 287 (Chothia) HCDR3 GSFYTRDSYFDV SEQ ID NO: 288 (Kabat) LCDR1TGTSSDVGTYNQVS SEQ ID NO: 289 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 290(Kabat) LCDR3 SSRDLIGHYV SEQ ID NO: 291 (Chothia) LCDR1 TSSDVGTYNQ SEQID NO: 292 (Chothia) LCDR2 GVS SEQ ID NO: 293 (Chothia) LCDR3 RDLIGHYSEQ ID NO: 294 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIDPHSGNAVYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO:295 VLDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 296 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGACATCGACCCGCATTCTGGCAACGCTGTTTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 297 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 298 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIDPHSGNAVYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 299 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 300 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGACATCGACCCGCATTCTGGCAACGCTGTTTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 301 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR12922 SEQ ID NO: 302 (Kabat) HCDR1 GYYMH SEQ ID NO:303 (Kabat) HCDR2 VIDPYSGWTEYAQKFQG SEQ ID NO: 304 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 305 (Chothia) HCDR1 GYTFTGY SEQ ID NO: 306(Chothia) HCDR2 DPYSGW SEQ ID NO: 307 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 308 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 309 (Kabat) LCDR2GVSKRPS SEQ ID NO: 310 (Kabat) LCDR3 SSRDLIGHYV SEQ ID NO: 311 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 312 (Chothia) LCDR2 GVS SEQ ID NO: 313(Chothia) LCDR3 RDLIGHY SEQ ID NO: 314 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGVIDPYSGWTEYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO:315 VLDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 316 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGTTATTGACCCGTACTCTGGCTGGACTGAATACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 317 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 318 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGVIDPYSGWTEYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 319 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 320 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCGTTATTGACCCGTACTCTGGCTGGACTGAATACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 321 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13654 SEQ ID NO: 322 (Kabat) HCDR1 SYDIH SEQ ID NO:323 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 324 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 325 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 326(Chothia) HCDR2 DPYSGN SEQ ID NO: 327 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 328 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 329 (Kabat) LCDR2GVSKRPS SEQ ID NO: 330 (Kabat) LCDR3 QSRGEYRPGWV SEQ ID NO: 331(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 332 (Chothia) LCDR2 GVS SEQ ID NO:333 (Chothia) LCDR3 RGEYRPGW SEQ ID NO: 334 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 335VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSRGEYRPGWVFGGGTKLTVL SEQ ID NO: 336 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 337 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGTCTCGTGGTGAATACCGTCCGGGTTGGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 338 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 339 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSVVYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSRGEYRPGWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 340 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 341 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGTCTCGTGGTGAATACCGTCCGGGTTGGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13655 SEQ ID NO: 342 (Kabat) HCDR1 SYDIH SEQ IDNO: 343 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 344 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 345 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 346(Chothia) HCDR2 DPYSGN SEQ ID NO: 347 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 348 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 349 (Kabat) LCDR2GVSKRPS SEQ ID NO: 350 (Kabat) LCDR3 SSATQKPDVTV SEQ ID NO: 351(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 352 (Chothia) LCDR2 GVS SEQ ID NO:353 (Chothia) LCDR3 ATQKPDVT SEQ ID NO: 354 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 355VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVL SEQ ID NO: 356 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 357 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 358 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 359 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 360 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 361 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13656 SEQ ID NO: 362 (Kabat) HCDR1 SYDIH SEQ IDNO: 363 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 364 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 365 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 366(Chothia) HCDR2 DPYSGN SEQ ID NO: 367 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 368 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 368 (Kabat) LCDR2GVSKRPS SEQ ID NO: 370 (Kabat) LCDR3 AVRDSVWHV SEQ ID NO: 371 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 372 (Chothia) LCDR2 GVS SEQ ID NO: 373(Chothia) LCDR3 RDSVWH SEQ ID NO: 374 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 375VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCAVRDSVWHVFGGGTKLTVL SEQ ID NO: 376 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 377 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTGTTCGTGACTCCGTTTGGCATGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 378 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 379 LightChain DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCAVRDSVWHVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 380 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 381 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTGTTCGTGACTCCGTTTGGCATGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13657 SEQ ID NO: 382 (Kabat) HCDR1 SYDIH SEQ ID NO: 383(Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 384 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 385 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 386(Chothia) HCDR2 DPYSGN SEQ ID NO: 387 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 388 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 389 (Kabat) LCDR2GVSKRPS SEQ ID NO: 390 (Kabat) LCDR3 SARDGWSEYV SEQ ID NO: 391 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 392 (Chothia) LCDR2 GVS SEQ ID NO: 393(Chothia) LCDR3 RDGWSEY SEQ ID NO: 394 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 395VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSARDGWSEYVFGGGTKLTVL SEQ ID NO: 396 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 397 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTGCTCGTGACGGTTGGTCTGAATACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 398 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGKSEQ ID NO: 399 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSARDGWSEYVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 400 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 401 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTGCTCGTGACGGTTGGTCTGAATACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13658 SEQ ID NO: 402 (Kabat) HCDR1 SYDIH SEQ ID NO:403 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 404 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 405 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 406(Chothia) HCDR2 DPYSGN SEQ ID NO: 407 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 408 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 409 (Kabat) LCDR2GVSKRPS SEQ ID NO: 410 (Kabat) LCDR3 ASADHSYHTV SEQ ID NO: 411 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 412 (Chothia) LCDR2 GVS SEQ ID NO: 413(Chothia) LCDR3 ADHSYHT SEQ ID NO: 414 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 415VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVL SEQ ID NO: 416 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 417 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 418 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 419 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 420 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 421 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13659 SEQ ID NO: 422 (Kabat) HCDR1 SYDIH SEQ ID NO:423 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 424 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 425 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 426(Chothia) HCDR2 DPYSGN SEQ ID NO: 427 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 428 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 429 (Kabat) LCDR2GVSKRPS SEQ ID NO: 430 (Kabat) LCDR3 GSRTSHNWV SEQ ID NO: 431 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 432 (Chothia) LCDR2 GVS SEQ ID NO: 433(Chothia) LCDR3 RTSHNW SEQ ID NO: 434 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 435VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCGSRTSHNWVFGGGTKLTVL SEQ ID NO: 436 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 437 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGGTTCTCGTACTTCTCATAACTGGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 438 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 439 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCGSRTSHNWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 440 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 441 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGGTTCTCGTACTTCTCATAACTGGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13660 SEQ ID NO: 442 (Kabat) HCDR1 SYDIH SEQ ID NO: 443(Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 444 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 445 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 446(Chothia) HCDR2 DPYSGN SEQ ID NO: 447 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 448 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 449 (Kabat) LCDR2GVSKRPS SEQ ID NO: 450 (Kabat) LCDR3 AVRGSQTLV SEQ ID NO: 451 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 452 (Chothia) LCDR2 GVS SEQ ID NO: 453(Chothia) LCDR3 RGSQTL SEQ ID NO: 454 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 455VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCAVRGSQTLVFGGGTKLTVL SEQ ID NO: 456 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 457 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTGTTCGTGGTTCTCAGACTCTGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 458 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 459 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCAVRGSQTLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 460 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 461 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTGTTCGTGGTTCTCAGACTCTGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13661 SEQ ID NO: 462 (Kabat) HCDR1 SYDIH SEQ ID NO: 463(Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 464 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 465 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 466(Chothia) HCDR2 DPYSGN SEQ ID NO: 467 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 468 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 469 (Kabat) LCDR2GVSKRPS SEQ ID NO: 470 (Kabat) LCDR3 GSRDSWAHV SEQ ID NO: 471 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 472 (Chothia) LCDR2 GVS SEQ ID NO: 473(Chothia) LCDR3 RDSWAH SEQ ID NO: 474 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 475VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCGSRDSWAHVFGGGTKLTVL SEQ ID NO: 476 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 477 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGGTTCTCGTGACTCTTGGGCTCATGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 478 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 479 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCGSRDSWAHVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 480 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 481 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGGTTCTCGTGACTCTTGGGCTCATGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13662 SEQ ID NO: 482 (Kabat) HCDR1 SYDIH SEQ ID NO: 483(Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 484 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 485 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 486(Chothia) HCDR2 DPYSGN SEQ ID NO: 487 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 488 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 489 (Kabat) LCDR2GVSKRPS SEQ ID NO: 490 (Kabat) LCDR3 YSRAKTHWTDV SEQ ID NO: 491(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 492 (Chothia) LCDR2 GVS SEQ ID NO:493 (Chothia) LCDR3 RAKTHWTD SEQ ID NO: 494 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 495VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCYSRAKTHWTDVFGGGTKLTVL SEQ ID NO: 496 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 497 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTACTCTCGTGCTAAAACTCATTGGACTGACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 498 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 499 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCYSRAKTHWTDVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 500 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 501 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTACTCTCGTGCTAAAACTCATTGGACTGACGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13663 SEQ ID NO: 502 (Kabat) HCDR1 SYDIH SEQ IDNO: 503 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 504 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 505 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 506(Chothia) HCDR2 DPYSGN SEQ ID NO: 507 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 508 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 509 (Kabat) LCDR2GVSKRPS SEQ ID NO: 510 (Kabat) LCDR3 SVWTSIKVFV SEQ ID NO: 511 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 512 (Chothia) LCDR2 GVS SEQ ID NO: 513(Chothia) LCDR3 WTSIKVF SEQ ID NO: 514 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 515VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSVWTSIKVFVFGGGTKLTVL SEQ ID NO: 516 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 517 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTGTTTGGACTTCTATCAAAGTTTTCGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 518 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 519 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSVWTSIKVFVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 520 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 521 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTGTTTGGACTTCTATCAAAGTTTTCGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13664 SEQ ID NO: 522 (Kabat) HCDR1 SYDIH SEQ ID NO:523 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 524 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 525 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 526(Chothia) HCDR2 DPYSGN SEQ ID NO: 527 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 528 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 529 (Kabat) LCDR2GVSKRPS SEQ ID NO: 530 (Kabat) LCDR3 SAYDASTQVV SEQ ID NO: 531 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 532 (Chothia) LCDR2 GVS SEQ ID NO: 533(Chothia) LCDR3 YDASTQV SEQ ID NO: 534 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 535VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSAYDASTQVVFGGGTKLTVL SEQ ID NO: 536 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 537 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTGCTTACGACGCTTCTACTCAGGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 538 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 539 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSAYDASTQVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 540 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 541 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTGCTTACGACGCTTCTACTCAGGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13665 SEQ ID NO: 542 (Kabat) HCDR1 SYDIH SEQ ID NO:543 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 544 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 545 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 546(Chothia) HCDR2 DPYSGN SEQ ID NO: 547 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 548 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 549 (Kabat) LCDR2GVSKRPS SEQ ID NO: 550 (Kabat) LCDR3 QSAAIATSV SEQ ID NO: 551 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 552 (Chothia) LCDR2 GVS SEQ ID NO: 553(Chothia) LCDR3 AAIATS SEQ ID NO: 554 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 555VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSAAIATSVFGGGTKLTVL SEQ ID NO: 556 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 557 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGTCTGCTGCTATCGCTACTTCTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 558 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 559 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSAAIATSVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 560 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 561 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGTCTGCTGCTATCGCTACTTCTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13666 SEQ ID NO: 562 (Kabat) HCDR1 SYDIH SEQ ID NO: 563(Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 564 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 565 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 566(Chothia) HCDR2 DPYSGN SEQ ID NO: 567 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 568 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 569 (Kabat) LCDR2GVSKRPS SEQ ID NO: 570 (Kabat) LCDR3 STTTYSFHMV SEQ ID NO: 571 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 572 (Chothia) LCDR2 GVS SEQ ID NO: 573(Chothia) LCDR3 TTYSFHM SEQ ID NO: 574 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 575VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSTTTYSFHMVFGGGTKLTVL SEQ ID NO: 576 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 577 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTACTACTACTTACTCTTTCCATATGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 578 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 579 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSTTTYSFHMVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 580 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 581 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTACTACTACTTACTCTTTCCATATGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13667 SEQ ID NO: 582 (Kabat) HCDR1 SYDIH SEQ ID NO:583 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 584 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 585 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 586(Chothia) HCDR2 DPYSGN SEQ ID NO: 587 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 588 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 589 (Kabat) LCDR2GVSKRPS SEQ ID NO: 590 (Kabat) LCDR3 QAWDYRQTIV SEQ ID NO: 591 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 592 (Chothia) LCDR2 GVS SEQ ID NO: 593(Chothia) LCDR3 WDYRQTI SEQ ID NO: 594 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 595VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQAWDYRQTIVFGGGTKLTVL SEQ ID NO: 596 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 597 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGCTTGGGACTACCGTCAGACTATCGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 598 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 599 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQAWDYRQTIVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 600 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 601 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGCTTGGGACTACCGTCAGACTATCGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13668 SEQ ID NO: 602 (Kabat) HCDR1 SYDIH SEQ ID NO:603 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 604 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 605 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 606(Chothia) HCDR2 DPYSGN SEQ ID NO: 607 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 608 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 609 (Kabat) LCDR2GVSKRPS SEQ ID NO: 610 (Kabat) LCDR3 QVWDSDQAMV SEQ ID NO: 611 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 612 (Chothia) LCDR2 GVS SEQ ID NO: 613(Chothia) LCDR3 WDSDQAM SEQ ID NO: 614 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 615VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQVWDSDQAMVFGGGTKLTVL SEQ ID NO: 616 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 617 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGTTTGGGACTCTGACCAGGCTATGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 618 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 619 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQVWDSDQAMVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 620 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 621 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGTTTGGGACTCTGACCAGGCTATGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13669 SEQ ID NO: 622 (Kabat) HCDR1 SYDIH SEQ ID NO:623 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 624 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 625 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 626(Chothia) HCDR2 DPYSGN SEQ ID NO: 627 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 628 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 629 (Kabat) LCDR2GVSKRPS SEQ ID NO: 630 (Kabat) LCDR3 STATAMTVSLV SEQ ID NO: 631(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 632 (Chothia) LCDR2 GVS SEQ ID NO:633 (Chothia) LCDR3 ATAMTVSL SEQ ID NO: 634 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 635VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSTATAMTVSLVFGGGTKLTVL SEQ ID NO: 636 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 637 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTACTGCTACTGCTATGACTGTTTCTCTGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 638 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 639 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSTATAMTVSLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 640 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 641 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTACTGCTACTGCTATGACTGTTTCTCTGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR13670 SEQ ID NO: 642 (Kabat) HCDR1 SYDIH SEQ IDNO: 643 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 644 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 645 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 646(Chothia) HCDR2 DPYSGN SEQ ID NO: 647 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 648 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 649 (Kabat) LCDR2GVSKRPS SEQ ID NO: 650 (Kabat) LCDR3 QVADQGWHQV SEQ ID NO: 651 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 652 (Chothia) LCDR2 GVS SEQ ID NO: 653(Chothia) LCDR3 ADQGWHQ SEQ ID NO: 654 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 655VL DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQVADQGWHQVFGGGTKLTVL SEQ ID NO: 656 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 657 DNA VLGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGTTGCTGACCAGGGTTGGCATCAGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 658 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 659 Light ChainDIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQVADQGWHQVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 660 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 661 DNA LightGATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCCAGGTTGCTGACCAGGGTTGGCATCAGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR14537 SEQ ID NO: 662 (Kabat) HCDR1 SYDIH SEQ ID NO:663 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 664 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 665 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 666(Chothia) HCDR2 DPYSGN SEQ ID NO: 667 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 668 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 669 (Kabat) LCDR2GVSKRPS SEQ ID NO: 670 (Kabat) LCDR3 SSATQKPDVTV SEQ ID NO: 671(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 672 (Chothia) LCDR2 GVS SEQ ID NO:673 (Chothia) LCDR3 ATQKPDVT SEQ ID NO: 674 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 675VL QSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVL SEQ ID NO: 676 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 677 DNA VLCAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 678 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 679 Light ChainQSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 680 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 681 DNA LightCAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA MOR14538 SEQ ID NO: 682 (Kabat) HCDR1 SYDIH SEQ IDNO: 683 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 684 (Kabat) HCDR3GSFYTRDSYFDV SEQ ID NO: 685 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 686(Chothia) HCDR2 DPYSGN SEQ ID NO: 687 (Chothia) HCDR3 GSFYTRDSYFDV SEQID NO: 688 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 689 (Kabat) LCDR2GVSKRPS SEQ ID NO: 690 (Kabat) LCDR3 ASADHSYHTV SEQ ID NO: 691 (Chothia)LCDR1 TSSDVGTYNQ SEQ ID NO: 692 (Chothia) LCDR2 GVS SEQ ID NO: 693(Chothia) LCDR3 ADHSYHT SEQ ID NO: 694 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID NO: 695VL QSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVL SEQ ID NO: 696 DNA VHCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 697 DNA VLCAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGCTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA SEQ ID NO: 698 Heavy ChainQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 699 Light ChainQSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 700 DNA HeavyCAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG ChainCTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGCCAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCTTACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 701 DNA LightCAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC ChainTGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCGGGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA

In one aspect, the present invention provides antibodies thatspecifically bind to domain 3 of HER3 protein (e.g., human and/orcynomologus HER3), the antibodies comprising a VH domain having an aminoacid sequence of SEQ ID NO: 14, 34, 54, 74, 94, 114, 134, 154, and 174.In another, the present invention provides antibodies that specificallybind specifically bind to domain 3 of HER3 protein (e.g., human and/orcynomologus HER3), the antibodies comprising a VL domain having an aminoacid sequence of SEQ ID NO: 15, 35, 55, 75, 95, 115, 135, 155, and 175.

In one aspect, the present invention provides antibodies thatspecifically bind to domains 3-4 of HER3 protein (e.g., human and/orcynomologus HER3), the antibodies comprising a VH domain having an aminoacid sequence of SEQ ID NO: 194, 214, 234, 254, 274, 294, 314, 334, 354,374, 394, 414, 434, 454, 474, 494, 514, 534, 554, 574, 594, 614, 634,654, 674, and 694. In another aspect, the present invention providesantibodies that specifically bind specifically bind to domain 3 of HER3protein (e.g., human and/or cynomologus HER3), the antibodies comprisinga VL domain having an amino acid sequence of SEQ ID NO: 195, 215, 235,255, 275, 295, 315, 335, 355, 375, 395, 415, 435, 455, 475, 495, 515,535, 555, 575, 595, 615, 635, 655, 675, and 695.

Since each of these antibodies or fragments thereof can bind to HER3,the VH, VL, full length light chain, and full length heavy chainsequences (amino acid sequences and the nucleotide sequences encodingthe amino acid sequences) can be “mixed and matched” to create otherHER3 antibodies of the invention. Such “mixed and matched” HER3antibodies can be tested using the binding assays known in the art(e.g., ELISAs, and other assays described in the Example section). Whenthese chains are mixed and matched, a VH sequence from a particularVH/VL pairing should be replaced with a structurally similar VHsequence. Likewise a full length heavy chain sequence from a particularfull length heavy chain/full length light chain pairing should bereplaced with a structurally similar full length heavy chain sequence.Likewise, a VL sequence from a particular VH/VL pairing should bereplaced with a structurally similar VL sequence. Likewise a full lengthlight chain sequence from a particular full length heavy chain/fulllength light chain pairing should be replaced with a structurallysimilar full length light chain sequence.

Accordingly, in one aspect, the invention provides an isolatedmonoclonal antibody or fragment thereof having: a heavy chain variableregion comprising an amino acid sequence selected from the groupconsisting of SEQ ID NO: 14, 34, 54, 74, 94, 114, 134, 154, and 174; anda light chain variable region comprising an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 15, 35, 55, 75, 95, 115, 135,155, and 175; wherein the antibody specifically binds to domain 3 ofHER3 (e.g., human and/or cynomologus).

Accordingly, in one aspect, the invention provides an isolatedmonoclonal antibody or fragment thereof having: a heavy chain variableregion comprising an amino acid sequence selected from the groupconsisting of SEQ ID NO: 194, 214, 234, 254, 274, 294, 314, 334, 354,374, 394, 414, 434, 454, 474, 494, 514, 534, 554, 574, 594, 614, 634,654, 674, and 694; and a light chain variable region comprising an aminoacid sequence selected from the group consisting of SEQ ID NOs: 195,215, 235, 255, 275, 295, 315, 335, 355, 375, 395, 415, 435, 455, 475,495, 515, 535, 555, 575, 595, 615, 635, 655, 675, and 695; wherein theantibody specifically binds to domain 3 of HER3 (e.g., human and/orcynomologus).

In a specific embodiment, an antibody that binds to domain 3 of HER3comprises a VH of SEQ ID NO. 14 and VL of SEQ ID NO: 15. In a specificembodiment, an antibody that binds to domain 3 of HER3 comprises a VH ofSEQ ID NO: 34 and VL of SEQ ID NO: 35. In a specific embodiment, anantibody that binds to domain 3 of HER3 comprises a VH of SEQ ID NO: 54and VL of SEQ ID NO: 55. In a specific embodiment, an antibody thatbinds to domain 3 of HER3 comprises a SEQ ID NO: 74 and VL of SEQ ID NO:75. In a specific embodiment, an antibody that binds to domain 3 of HER3comprises a VH of SEQ ID NO: 94 and VL of SEQ ID NO: 95. In a specificembodiment, an antibody that binds to domain 3 of HER3 comprises a VH ofSEQ ID NO: 114 and VL of SEQ ID NO: 115. In a specific embodiment, anantibody that binds to domain 3 of HER3 comprises a VH of SEQ ID NO: 134and VL of SEQ ID NO: 135. In a specific embodiment, an antibody thatbinds to domain 3 of HER3 comprises a VH of SEQ ID NO: 154 and VL of SEQID NO: 155. In a specific embodiment, an antibody that binds to domain 3of HER3 comprises a VH of SEQ ID NO: 174 and VL of SEQ ID NO: 175.

In a specific embodiment, an antibody that binds to domains 3-4 of HER3comprises a VH of SEQ ID NO. 194 and VL of SEQ ID NO: 195. In a specificembodiment, an antibody that binds to domains 3-4 of HER3 comprises a VHof SEQ ID NO: 214 and VL of SEQ ID NO: 215. In a specific embodiment, anantibody that binds to domains 3-4 of HER3 comprises a VH of SEQ ID NO:234 and VL of SEQ ID NO: 235. In a specific embodiment, an antibody thatbinds to domains 3-4 of HER3 comprises a SEQ ID NO: 254 and VL of SEQ IDNO: 255.

In a specific embodiment, an antibody that binds to domains 3-4 of HER3comprises a VH of SEQ ID NO: 274 and VL of SEQ ID NO: 275. In a specificembodiment, an antibody that binds to domains 3-4 of HER3 comprises a VHof SEQ ID NO: 294 and VL of SEQ ID NO: 295. In a specific embodiment, anantibody that binds to domains 3-4 of HER3 comprises a VH of SEQ ID NO:314 and VL of SEQ ID NO: 315. In a specific embodiment, an antibody thatbinds to domains 3-4 of HER3 comprises a VH of SEQ ID NO: 334 and VL ofSEQ ID NO: 335. In a specific embodiment, an antibody that binds todomains 3-4 of HER3 comprises a VH of SEQ ID NO: 354 and VL of SEQ IDNO: 355. In a specific embodiment, an antibody that binds to domains 3-4of HER3 comprises a VH of SEQ ID NO: 374 and VL of SEQ ID NO: 375. In aspecific embodiment, an antibody that binds to domains 3-4 of HER3comprises a VH of SEQ ID NO: 394 and VL of SEQ ID NO: 395. In a specificembodiment, an antibody that binds to domains 3-4 of HER3 comprises a VHof SEQ ID NO: 414 and VL of SEQ ID NO: 415. In a specific embodiment, anantibody that binds to domains 3-4 of HER3 comprises a VH of SEQ ID NO:434 and VL of SEQ ID NO: 435. In a specific embodiment, an antibody thatbinds to domains 3-4 of HER3 comprises a VH of SEQ ID NO: 454 and VL ofSEQ ID NO: 255. In a specific embodiment, an antibody that binds todomains 3-4 of HER3 comprises a VH of SEQ ID NO: 474 and VL of SEQ IDNO: 475. In a specific embodiment, an antibody that binds to domains 3-4of HER3 comprises a VH of SEQ ID NO: 494 and VL of SEQ ID NO: 495. In aspecific embodiment, an antibody that binds to domains 3-4 of HER3comprises a VH of SEQ ID NO: 514 and VL of SEQ ID NO: 515. In a specificembodiment, an antibody that binds to domains 3-4 of HER3 comprises a VHof SEQ ID NO: 534 and VL of SEQ ID NO: 535. In a specific embodiment, anantibody that binds to domains 3-4 of HER3 comprises a VH of SEQ ID NO:554 and VL of SEQ ID NO: 555. In a specific embodiment, an antibody thatbinds to domains 3-4 of HER3 comprises a VH of SEQ ID NO: 574 and VL ofSEQ ID NO: 575. In a specific embodiment, an antibody that binds todomains 3-4 of HER3 comprises a VH of SEQ ID NO: 594 and VL of SEQ IDNO: 595. In a specific embodiment, an antibody that binds to domains 3-4of HER3 comprises a VH of SEQ ID NO: 614 and VL of SEQ ID NO: 615. In aspecific embodiment, an antibody that binds to domains 3-4 of HER3comprises a VH of SEQ ID NO: 634 and VL of SEQ ID NO: 635. In a specificembodiment, an antibody that binds to domains 3-4 of HER3 comprises a VHof SEQ ID NO: 654 and VL of SEQ ID NO: 655. In a specific embodiment, anantibody that binds to domains 3-4 of HER3 comprises a VH of SEQ ID NO:674 and VL of SEQ ID NO: 675. In a specific embodiment, an antibody thatbinds to domains 3-4 of HER3 comprises a VH of SEQ ID NO: 694 and VL ofSEQ ID NO: 695.

In another aspect, the present invention provides HER3 antibodies thatbind to domain 3 that comprise the heavy chain and light chain CDR1s,CDR2s and CDR3s as described in Table 1, or combinations thereof. Theamino acid sequences of the VH CDR1s of the antibodies are shown in SEQID NOs: 2, 22, 42, 62, 82, 102, 122, 142, and 162. The amino acidsequences of the VH CDR2s of the antibodies and are shown in SEQ ID NOs:3, 23, 43, 63, 83, 103, 123, 143, and 163. The amino acid sequences ofthe VH CDR3s of the antibodies are shown in SEQ ID NOs: 4, 24, 44, 64,84, 104, 124, 144, and 164. The amino acid sequences of the VL CDR1s ofthe antibodies are shown in SEQ ID NOs: 8, 28, 48, 68, 88, 108, 128,148, and 168. The amino acid sequences of the VL CDR2s of the antibodiesare shown in SEQ ID NOs: 9, 29, 49, 69, 89, 109, 129, 149, and 169. Theamino acid sequences of the VL CDR3s of the antibodies are shown in SEQID NOs: 10, 30, 50, 70, 90, 110, 130, 150, and 170. The CDR regions aredelineated using the Kabat system (Kabat et al., (1991) Sequences ofProteins of Immunological Interest, Fifth Edition, U.S. Department ofHealth and Human Services, NIH Publication No. 91-3242; Chothia et al.,(1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:877-883; and Al-Lazikani et al., (1997) J. Mol. Biol. 273, 927-948).

In a specific embodiment, an antibody that binds to domain 3 of HER3comprises a heavy chain variable region CDR1 of SEQ ID NO: 142; a CDR2of SEQ ID NO: 143; a CDR3 of SEQ ID NO: 144; a light chain variableregion CDR1 of SEQ ID NO: 148; a CDR2 of SEQ ID NO: 149; and a CDR3 ofSEQ ID NO: 150.

In a specific embodiment, an antibody that binds to domain 3 of HER3comprises a heavy chain variable region CDR1 of SEQ ID NO: 162; a CDR2of SEQ ID NO: 163; a CDR3 of SEQ ID NO: 164; a light chain variableregion CDR1 of SEQ ID NO: 168; a CDR2 of SEQ ID NO: 169; and a CDR3 ofSEQ ID NO: 170.

In another aspect, the present invention provides HER3 antibodies thatbind to domains 3-4 that comprise the heavy chain and light chain CDR1s,CDR2s and CDR3s as described in Table 2, or combinations thereof. Theamino acid sequences of the VH CDR1s of the antibodies are shown in SEQID NOs: 182, 202, 222, 242, 262, 282, 302, 322, 342, 362, 382, 402, 422,442, 462, 482, 502, 522, 542, 562, 582, 602, 622, 642, 662, and 682. Theamino acid sequences of the VH CDR2s of the antibodies and are shown inSEQ ID NOs: 183, 203, 223, 243, 263, 283, 303, 323, 343, 363, 383, 403,423, 443, 463, 483, 503, 523, 543, 563, 583, 603, 623, 643, 663, and683. The amino acid sequences of the VH CDR3s of the antibodies areshown in SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304, 324, 344, 364,384, 404, 424, 444, 464, 484, 504, 524, 544, 564, 584, 604, 624, 644,664, and 684. The amino acid sequences of the VL CDR1s of the antibodiesare shown in SEQ ID NOs: 188, 208, 228, 248, 268, 288, 308, 328, 348,368, 388, 408, 428, 448, 468, 488, 508, 528, 548, 568, 588, 608, 628,648, 668, and 688. The amino acid sequences of the VL CDR2s of theantibodies are shown in SEQ ID NOs: 189, 209, 229, 249, 269, 289, 309,329, 349, 369, 389, 409, 429, 449, 469, 489, 509, 529, 549, 569, 589,609, 629, 649, 669, and 689. The amino acid sequences of the VL CDR3s ofthe antibodies are shown in SEQ ID NOs: 190, 210, 230, 250, 270, 290,310, 330, 350, 370, 390, 410, 430, 450, 470, 490, 510, 530, 550, 570,590, 610, 630, 650, 670, and 690. The CDR regions are delineated usingthe Kabat system (Kabat et al., (1991) Sequences of Proteins ofImmunological Interest, Fifth Edition, U.S. Department of Health andHuman Services, NIH Publication No. 91-3242; Chothia et al., (1987) J.Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342: 877-883; andAl-Lazikani et al., (1997) J. Mol. Biol. 273, 927-948).

In a specific embodiment, an antibody that binds to domains 3-4 of HER3comprises a heavy chain variable region CDR1 of SEQ ID NO: 662; a CDR2of SEQ ID NO: 663; a CDR3 of SEQ ID NO: 664; a light chain variableregion CDR1 of SEQ ID NO: 668; a CDR2 of SEQ ID NO: 669; and a CDR3 ofSEQ ID NO: 670.

In a specific embodiment, an antibody that binds to domains 3-4 of HER3comprises a heavy chain variable region CDR1 of SEQ ID NO: 682; a CDR2of SEQ ID NO: 683; a CDR3 of SEQ ID NO: 684; a light chain variableregion CDR1 of SEQ ID NO: 688; a CDR2 of SEQ ID NO: 689; and a CDR3 ofSEQ ID NO: 690.

Other antibodies of the invention include amino acids that have beenmutated, yet have at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%or 99% identity in the CDR regions with the CDR regions depicted in thesequences described in Table 1 or Table 2. In some embodiments, itincludes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or5 amino acids have been mutated in the CDR regions when compared withthe CDR regions depicted in the sequence described Table 1 or Table 2,while still maintaining their specificity for the original antibody'sepitope

Other antibodies of the invention include amino acids that have beenmutated, yet have at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%or 99% identity in the framework regions with the framework regionsdepicted in the sequences described in Table 1 or Table 2. In someembodiments, it includes mutant amino acid sequences wherein no morethan 1, 2, 3, 4, 5, 6, or 7 amino acids have been mutated in theframework regions when compared with the framework regions depicted inthe sequence described Table 1 or Table 2, while still maintaining theirspecificity for the original antibody's epitope. The present inventionalso provides nucleic acid sequences that encode VH, VL, the full lengthheavy chain, and the full length light chain of the antibodies thatspecifically bind to a HER3 protein (e.g., human and/or cynomologusHER3).

Other antibodies of the invention include those where the amino acids ornucleic acids encoding the amino acids have been mutated, yet have atleast 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identity to thesequences described in Table 1 or Table 2. In some embodiments, itinclude mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5amino acids have been mutated in the variable regions when compared withthe variable regions depicted in the sequence described in Table 1 orTable 2, while retaining substantially the same therapeutic activity.

As used herein, a human antibody comprises heavy or light chain variableregions or full length heavy or light chains that are “the product of”or “derived from” a particular germline sequence if the variable regionsor full length chains of the antibody are obtained from a system thatuses human germline immunoglobulin genes. Such systems includeimmunizing a transgenic mouse carrying human immunoglobulin genes withthe antigen of interest or screening a human immunoglobulin gene librarydisplayed on phage with the antigen of interest. A human antibody thatis “the product of” or “derived from” a human germline immunoglobulinsequence can be identified as such by comparing the amino acid sequenceof the human antibody to the amino acid sequences of human germlineimmunoglobulins and selecting the human germline immunoglobulin sequencethat is closest in sequence (i.e., greatest % identity) to the sequenceof the human antibody. A human antibody that is “the product of” or“derived from” a particular human germline immunoglobulin sequence maycontain amino acid differences as compared to the germline sequence, dueto, for example, naturally occurring somatic mutations or intentionalintroduction of site-directed mutations. However, in the VH or VLframework regions, a selected human antibody typically is at least 90%identical in amino acids sequence to an amino acid sequence encoded by ahuman germline immunoglobulin gene and contains amino acid residues thatidentify the human antibody as being human when compared to the germlineimmunoglobulin amino acid sequences of other species (e.g., murinegermline sequences). In certain cases, a human antibody may be at least50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical in aminoacid sequence to the amino acid sequence encoded by the germlineimmunoglobulin gene. Typically, a recombinant human antibody willdisplay no more than 10 amino acid differences from the amino acidsequence encoded by the human germline immunoglobulin gene in the VH orVL framework regions. In certain cases, the human antibody may displayno more than 5, or even no more than 4, 3, 2, or 1 amino acid differencefrom the amino acid sequence encoded by the germline immunoglobulingene.

The antibodies disclosed herein can be derivatives of single chainantibodies, diabodies, domain antibodies, nanobodies, and unibodies. A“single-chain antibody” (scFv) consists of a single polypeptide chaincomprising a VL domain linked to a VH domain, wherein VL domain and VHdomain are paired to form a monovalent molecule. Single chain antibodycan be prepared according to method known in the art (see, for example,Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc.Natl. Acad. Sci. USA 85:5879-5883). A “disbud” consists of two chains,each chain comprising a heavy chain variable region connected to a lightchain variable region on the same polypeptide chain connected by a shortpeptide linker, wherein the two regions on the same chain do not pairwith each other but with complementary domains on the other chain toform a bispecific molecule. Methods of preparing diabodies are known inthe art (See, e.g., Holliger et al., (1993) Proc. Natl. Acad. Sci. USA90:6444-6448, and Poljak et al., (1994) Structure 2:1121-1123). Domainantibodies (dAbs) are small functional binding units of antibodies,corresponding to the variable regions of either the heavy or lightchains of antibodies. Domain antibodies are well expressed in bacterial,yeast, and mammalian cell systems. Further details of domain antibodiesand methods of production thereof are known in the art (see, forexample, U.S. Pat. Nos. 6,291,158; 6,582,915; 6,593,081; 6,172,197;6,696,245; European Patents 0368684 & 0616640; WO05/035572, WO04/101790,WO04/081026, WO04/058821, WO04/003019 and WO03/002609. Nanobodies arederived from the heavy chains of an antibody. A nanobody typicallycomprises a single variable domain and two constant domains (CH2 andCH3) and retains antigen-binding capacity of the original antibody.Nanobodies can be prepared by methods known in the art (See e.g., U.S.Pat. No. 6,765,087, U.S. Pat. No. 6,838,254, WO 06/079372). Unibodiesconsist of one light chain and one heavy chain of a IgG4 antibody.Unibodies may be made by the removal of the hinge region of IgG4antibodies. Further details of unibodies and methods of preparing themmay be found in WO2007/059782.

Homologous Antibodies

In yet another embodiment, the present invention provides an antibody orfragment thereof comprising amino acid sequences that are homologous tothe sequences described in Table 1 or Table 2, and said antibody bindsto a HER3 protein (e.g., human and/or cynomologus HER3), and retains thedesired functional properties of those antibodies described in Table 1or Table 2.

For example, the invention provides an isolated monoclonal antibody (ora functional fragment thereof) comprising a heavy chain variable regionand a light chain variable region, wherein the heavy chain variableregion comprises an amino acid sequence that is at least 80%, 90%, 95%,96%, 97%, 98% or 99% identical to an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 14, 34, 54, 74, 94, 114, 134, 154,and 174; the light chain variable region comprises an amino acidsequence that is at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identicalto an amino acid sequence selected from the group consisting of SEQ IDNOs: 15, 35, 55, 75, 95, 115, 135, 155, and 175; wherein the antibodybinds to domain 3 of HER3 (e.g., human and/or cynomologus HER3) andinhibits the signaling activity of HER3, which can be measured in aphosphorylation assay or other measure of HER signaling (e.g.,phospho-HER3 assays, phospho-Akt assays, cell proliferation, and ligandblocking assays as described in the Examples). Also includes within thescope of the invention are variable heavy and light chain parentalnucleotide sequences; and full length heavy and light chain sequencesoptimized for expression in a mammalian cell. Other antibodies of theinvention include amino acids or nucleic acids that have been mutated,yet have at least 60, 70, 80, 90, 95, 98, or 99% percent identity to thesequences described above. In some embodiments, it include mutant aminoacid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids havebeen mutated by amino acid deletion, insertion or substitution in thevariable regions when compared with the variable regions depicted in thesequence described above.

For example, the invention provides an isolated monoclonal antibody (ora functional fragment thereof) comprising a heavy chain variable regionand a light chain variable region,

wherein the heavy chain variable region comprises an amino acid sequencethat is at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to anamino acid sequence selected from the group consisting of SEQ ID NOs:194, 214, 234, 254, 274, 294, 314, 334, 354, 374, 394, 414, 434, 454,474, 494, 514, 534, 554, 574, 594, 614, 634, 654, 674, and 694; thelight chain variable region comprises an amino acid sequence that is atleast 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to an amino acidsequence selected from the group consisting of SEQ ID NOs: 195, 215,235, 255, 275, 295, 315, 335, 355, 375, 395, 415, 435, 455, 475, 495,515, 535, 555, 575, 595, 615, 635, 655, 675, and 695; wherein theantibody binds to domains 3-4 of HER3 (e.g., human and/or cynomologusHER3) and inhibits the signaling activity of HER3, which can be measuredin a phosphorylation assay or other measure of HER signaling (e.g.,phospho-HER3 assays, phospho-Akt assays, cell proliferation, and ligandblocking assays as described in the Examples). Also includes within thescope of the invention are variable heavy and light chain parentalnucleotide sequences; and full length heavy and light chain sequencesoptimized for expression in a mammalian cell. Other antibodies of theinvention include amino acids or nucleic acids that have been mutated,yet have at least 60, 70, 80, 90, 95, 98, or 99% percent identity to thesequences described above. In some embodiments, it include mutant aminoacid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids havebeen mutated by amino acid deletion, insertion or substitution in thevariable regions when compared with the variable regions depicted in thesequence described above.

In other embodiments, the VH and/or VL amino acid sequences may be 50%,60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequencesset forth in Table 1 or Table 2. In other embodiments, the VH and/or VLamino acid sequences may be identical except an amino acid substitutionin no more than 1, 2, 3, 4 or 5 amino acid position. An antibody havingVH and VL regions having high (i.e., 80% or greater) identity to the VHand VL regions of the antibodies described in Table 1 or Table 2 can beobtained by mutagenesis (e.g., site-directed or PCR-mediatedmutagenesis), followed by testing of the encoded altered antibody forretained function using the functional assays described herein.

In other embodiments, the variable regions of heavy chain and/or lightchain nucleotide sequences may be 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%or 99% identical to the sequences set forth above.

As used herein, “percent identity” between the two sequences is afunction of the number of identical positions shared by the sequences(i.e., % identity equals number of identical positions/total number ofpositions×100), taking into account the number of gaps, and the lengthof each gap, which needs to be introduced for optimal alignment of thetwo sequences. The comparison of sequences and determination of percentidentity between two sequences can be accomplished using a mathematicalalgorithm, as described in the non-limiting examples below.

Additionally or alternatively, the protein sequences of the presentinvention can further be used as a “query sequence” to perform a searchagainst public databases to, for example, identifies related sequences.For example, such searches can be performed using the BLAST program(version 2.0) of Altschul et al., (1990) J. Mol. Biol. 215:403-10.

Antibodies with Conservative Modifications

In certain embodiments, an antibody of the invention has a heavy chainvariable region comprising CDR1, CDR2, and CDR3 sequences and a lightchain variable region comprising CDR1, CDR2, and CDR3 sequences, whereinone or more of these CDR sequences have specified amino acid sequencesbased on the antibodies described herein or conservative modificationsthereof, and wherein the antibodies retain the desired functionalproperties of the HER3 antibodies of the invention.

Accordingly, the invention provides an isolated HER3 monoclonalantibody, or a fragment thereof that bind to domain 3 of HER3,consisting of a heavy chain variable region comprising CDR1, CDR2, andCDR3 sequences and a light chain variable region comprising CDR1, CDR2,and CDR3 sequences, wherein: the heavy chain variable region CDR1 aminoacid sequences are selected from the group consisting of SEQ ID NOs: 2,22, 42, 62, 82, 102, 122, 142, and 162, and conservative modificationsthereof; the heavy chain variable region CDR2 amino acid sequences areselected from the group consisting of SEQ ID NOs: 3, 23, 43, 63, 83,103, 123, 143, and 163 and conservative modifications thereof; the heavychain variable region CDR3 amino acid sequences are selected from thegroup consisting of SEQ ID NOs: 4, 24, 44, 64, 84, 104, 124, 144, and164 and conservative modifications thereof; the light chain variableregions CDR1 amino acid sequences are selected from the group consistingof SEQ ID NOs: 8, 28, 48, 68, 88, 108, 128, 148, and 168 andconservative modifications thereof; the light chain variable regionsCDR2 amino acid sequences are selected from the group consisting of SEQID NOs: 9, 29, 49, 69, 89, 109, 129, 149, and 169, and conservativemodifications thereof; the light chain variable regions of CDR3 aminoacid sequences are selected from the group consisting of SEQ ID NOs: 10,30, 50, 70, 90, 110, 130, 150, and 170, and conservative modificationsthereof; the antibody or fragment thereof specifically binds to HER3,and inhibits HER3 activity by inhibiting a HER3 signaling pathway, whichcan be measured in a phosphorylation assay or other measure of HERsignaling (e.g., phospho-HER3 assays, phospho-Akt assays, cellproliferation, and ligand blocking assays as described in the Examples).

Accordingly, the invention provides an isolated HER3 monoclonalantibody, or a fragment thereof that bind to domains 3-4 of HER3,consisting of a heavy chain variable region comprising CDR1, CDR2, andCDR3 sequences and a light chain variable region comprising CDR1, CDR2,and CDR3 sequences, wherein: the heavy chain variable region CDR1 aminoacid sequences are selected from the group consisting of SEQ ID NOs:182, 202, 222, 242, 262, 282, 302, 322, 342, 362, 382, 402, 422, 442,462, 482, 502, 522, 542, 562, 582, 602, 622, 642, 662, and 682, andconservative modifications thereof; the heavy chain variable region CDR2amino acid sequences are selected from the group consisting of SEQ IDNOs: 183, 203, 223, 243, 263, 283, 303, 323, 343, 363, 383, 403, 423,443, 463, 483, 503, 523, 543, 563, 583, 603, 623, 643, 663, and 683 andconservative modifications thereof; the heavy chain variable region CDR3amino acid sequences are selected from the group consisting of SEQ IDNOs: 184, 204, 224, 244, 264, 284, 304, 324, 344, 364, 384, 404, 424,444, 464, 484, 504, 524, 544, 564, 584, 604, 624, 644, 664, and 684 andconservative modifications thereof; the light chain variable regionsCDR1 amino acid sequences are selected from the group consisting of SEQID NOs: 188, 208, 228, 248, 268, 288, 308, 328, 348, 368, 388, 408, 428,448, 468, 488, 508, 528, 548, 568, 588, 608, 628, 648, 668, and 688 andconservative modifications thereof; the light chain variable regionsCDR2 amino acid sequences are selected from the group consisting of SEQID NOs: 189, 209, 229, 249, 269, 289, 309, 329, 349, 369, 389, 409, 429,449, 469, 489, 509, 529, 549, 569, 589, 609, 629, 649, 669, and 689, andconservative modifications thereof; the light chain variable regions ofCDR3 amino acid sequences are selected from the group consisting of SEQID NOs: 190, 210, 230, 250, 270, 290, 310, 330, 350, 370, 390, 410, 430,450, 470, 490, 510, 530, 550, 570, 590, 610, 630, 650, 670, and 690, andconservative modifications thereof; the antibody or fragment thereofspecifically binds to HER3, and inhibits HER3 activity by inhibiting aHER3 signaling pathway, which can be measured in a phosphorylation assayor other measure of HER signaling (e.g., phospho-HER3 assays,phospho-Akt assays, cell proliferation, and ligand blocking assays asdescribed in the Examples).

Antibodies That Bind to the Same Epitope

The present invention provides antibodies that interacts with (e.g., bybinding, steric hindrance, stabilizing/destabilizing, spatialdistribution) the same epitope as do the HER3 antibodies described inTable 1 or Table 2. Additional antibodies can therefore be identifiedbased on their ability to cross-compete (e.g., to competitively inhibitthe binding of, in a statistically significant manner) with otherantibodies of the invention in HER3 binding assays. The ability of atest antibody to inhibit the binding of antibodies of the presentinvention to a HER3 protein (e.g., human and/or cynomologus HER3)demonstrates that the test antibody can compete with that antibody forbinding to HER3; such an antibody may, according to non-limiting theory,bind to the same or a related (e.g., a structurally similar or spatiallyproximal) epitope on the HER3 protein as the antibody with which itcompetes. In a certain embodiment, the antibody that binds to the sameepitope on HER3 as the antibodies of the present invention is a humanmonoclonal antibody. Such human monoclonal antibodies can be preparedand isolated as described herein.

In one embodiment, the antibody or fragments thereof binds to domain 3of HER3 and inhibits both ligand dependent and ligand-independent HER3signal transduction. In one embodiment, the antibody or fragmentsthereof bind to domains 3-4 of HER3 and inhibits both ligand dependentand ligand-independent HER3 signal transduction.

The antibodies of the invention or fragments thereof inhibit both liganddependent and independent activation of HER3 without preventing ligandbinding. This is considered advantageous for the following reasons:

(i) The therapeutic antibody would have clinical utility in a broadspectrum of tumors than an antibody which targeted a single mechanism ofHER3 activation (i.e. ligand dependent or ligand independent) sincedistinct tumor types are driven by each mechanism.

(ii) The therapeutic antibody would be efficacious in tumor types whereboth mechanisms of HER3 activation are simultaneously involved. Anantibody targeting a single mechanism of HER3 activation (i.e. liganddependent or ligand independent) would display little or no efficacy inthese tumor types

(iii) The efficacy of an antibody which inhibits ligand dependentactivation of HER3 without preventing ligand binding would be lesslikely to be adversely affected by increasing concentrations of ligand.This would translate to either increased efficacy in a tumor type drivenby very high concentrations of HER3 ligand or a reduced drug resistanceliability where resistance is mediated by up-regulation of HER3 ligands.

(iv) An antibody which inhibits HER3 activation by stabilizing theinactive form would be less prone to drug resistance driven byalternative mechanisms of HER3 activation.

Consequently, the antibodies of the invention may be used to treatconditions where existing therapeutic antibodies are clinicallyineffective.

Engineered and Modified Antibodies

An antibody of the invention further can be prepared using an antibodyhaving one or more of the VH and/or VL sequences shown herein asstarting material to engineer a modified antibody, which modifiedantibody may have altered properties from the starting antibody. Anantibody can be engineered by modifying one or more residues within oneor both variable regions (i.e., VH and/or VL), for example within one ormore CDR regions and/or within one or more framework regions.Additionally or alternatively, an antibody can be engineered bymodifying residues within the constant region(s), for example to alterthe effector function(s) of the antibody.

One type of variable region engineering that can be performed is CDRgrafting. Antibodies interact with target antigens predominantly throughamino acid residues that are located in the six heavy and light chaincomplementarity determining regions (CDRs). For this reason, the aminoacid sequences within CDRs are more diverse between individualantibodies than sequences outside of CDRs. Because CDR sequences areresponsible for most antibody-antigen interactions, it is possible toexpress recombinant antibodies that mimic the properties of specificnaturally occurring antibodies by constructing expression vectors thatinclude CDR sequences from the specific naturally occurring antibodygrafted onto framework sequences from a different antibody withdifferent properties (see, e.g., Riechmann et al., (1998) Nature332:323-327; Jones et al., (1986) Nature 321:522-525; Queen et al.,(1989) Proc. Natl. Acad., U.S.A. 86:10029-10033; U.S. Pat. No. 5,225,539to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and6,180,370 to Queen et al.)

Accordingly, another embodiment of the invention pertains to an isolatedHER3 monoclonal antibody, or fragment thereof that binds to domain 3 ofHER3, comprising a heavy chain variable region comprising CDR1 sequenceshaving an amino acid sequence selected from the group consisting of SEQID NOs: 2, 22, 42, 62, 82, 102, 122, 142, and 162; CDR2 sequences havingan amino acid sequence selected from the group consisting of SEQ ID NOs:33, 23, 43, 63, 83, 103, 123, 143, and 163; CDR3 sequences having anamino acid sequence selected from the group consisting of SEQ ID NOs: 4,24, 44, 64, 84, 104, 124, 144, and 164, respectively; and a light chainvariable region having CDR1 sequences having an amino acid sequenceselected from the group consisting of SEQ ID NOs: 8, 28, 48, 68, 88,108, 128, 148, and 168; CDR2 sequences having an amino acid sequenceselected from the group consisting of SEQ ID NOs: 9, 29, 49, 69, 89,109, 129, 149, and 169; and CDR3 sequences consisting of an amino acidsequence selected from the group consisting of SEQ ID NOs: 10, 30, 50,70, 90, 110, 130, 150, and 170, respectively.

Accordingly, another embodiment of the invention pertains to an isolatedHER3 monoclonal antibody, or fragment thereof that bind to domains 3-4of HER3, comprising a heavy chain variable region comprising CDR1sequences having an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 182, 202, 222, 242, 262, 282, 302, 322, 342,362, 382, 402, 422, 442, 462, 482, 502, 522, 542, 562, 582, 602, 622,642, 662, and 682; CDR2 sequences having an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 183, 203, 223, 243, 263, 283,303, 323, 343, 363, 383, 403, 423, 443, 463, 483, 503, 523, 543, 563,583, 603, 623, 643, 663, and 683; CDR3 sequences having an amino acidsequence selected from the group consisting of SEQ ID NOs: 184, 204,224, 244, 264, 284, 304, 324, 344, 364, 384, 404, 424, 444, 464, 484,504, 524, 544, 564, 584, 604, 624, 644, 664, and 684, respectively; anda light chain variable region having CDR1 sequences having an amino acidsequence selected from the group consisting of SEQ ID NOs: 188, 208,228, 248, 268, 288, 308, 328, 348, 368, 388, 408, 428, 448, 468, 488,508, 528, 548, 568, 588, 608, 628, 648, 668, and 688; CDR2 sequenceshaving an amino acid sequence selected from the group consisting of SEQID NOs: 189, 209, 229, 249, 269, 289, 309, 329, 349, 369, 389, 409, 429,449, 469, 489, 509, 529, 549, 569, 589, 609, 629, 649, 669, and 689; andCDR3 sequences consisting of an amino acid sequence selected from thegroup consisting of SEQ ID NOs: 190, 210, 230, 250, 270, 290, 310, 330,350, 370, 390, 410, 430, 450, 470, 490, 510, 530, 550, 570, 590, 610,630, 650, 670, and 690, respectively.

Such antibodies contain the VH and VL CDR sequences of monoclonalantibodies, yet may contain different framework sequences from theseantibodies. Such framework sequences can be obtained from public DNAdatabases or published references that include germline antibody genesequences. For example, germline DNA sequences for human heavy and lightchain variable region genes can be found in the “Vbase” human germlinesequence database (available on the Internet atwww.mrc-cpe.cam.ac.uk/vbase), as well as in Kabat et al., (1991)Sequences of Proteins of Immunological Interest, Fifth Edition, U.S.Department of Health and Human Services, NIH Publication No. 91-3242;Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989)Nature 342:877-883; and Al-Lazikani et al., (1997) J. Mol. Biol.273:927-948; Tomlinson et al., (1992) J. fol. Biol. 227:776-798; and Coxet al., (1994) Eur. J. Immunol. 24:827-836; the contents of each ofwhich are expressly incorporated herein by reference.

An example of framework sequences for use in the antibodies of theinvention are those that are structurally similar to the frameworksequences used by selected antibodies of the invention, e.g., consensussequences and/or framework sequences used by monoclonal antibodies ofthe invention. The VH CDR1, 2 and 3 sequences, and the VL CDR1, 2 and 3sequences, can be grafted onto framework regions that have the identicalsequence as that found in the germline immunoglobulin gene from whichthe framework sequence derive, or the CDR sequences can be grafted ontoframework regions that contain one or more mutations as compared to thegermline sequences. For example, it has been found that in certaininstances it is beneficial to mutate residues within the frameworkregions to maintain or enhance the antigen binding ability of theantibody (see e.g., U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and6,180,370 to Queen et al).

Another type of variable region modification is to mutate amino acidresidues within the VH and/or VL CDR1, CDR2 and/or CDR3 regions tothereby improve one or more binding properties (e.g., affinity) of theantibody of interest, known as “affinity maturation.” Site-directedmutagenesis or PCR-mediated mutagenesis can be performed to introducethe mutation(s) and the effect on antibody binding, or other functionalproperty of interest, can be evaluated in in vitro or in vivo assays asdescribed herein and provided in the Examples. Conservativemodifications (as discussed above) can be introduced. The mutations maybe amino acid substitutions, additions or deletions. Moreover, typicallyno more than one, two, three, four or five residues within a CDR regionare altered.

Accordingly, in another embodiment, the invention provides isolated HER3monoclonal antibodies, or fragment thereof that bind to domain 3 ofHER3, consisting of a heavy chain variable region having: a VH CDR1region consisting of an amino acid sequence selected from the grouphaving SEQ ID NOs: 22, 22, 42, 62, 82, 102, 122, 142, and 162 or anamino acid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions as compared to SEQ ID NOs: 2, 22,42, 62, 82, 102, 122, 142, and 162; a VH CDR2 region having an aminoacid sequence selected from the group consisting of SEQ ID NOs: 3, 23,43, 63, 83, 103, 123, 143, and 163 or an amino acid sequence having one,two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 3, 23, 43, 63, 83, 103, 123, 143,and 163; a VH CDR3 region having an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 4, 24, 44, 64, 84, 104, 124, 144,and 164, or an amino acid sequence having one, two, three, four or fiveamino acid substitutions, deletions or additions as compared to SEQ IDNOs: 4, 24, 44, 64, 84, 104, 124, 144, and 164, and 370; a VL CDR1region having an amino acid sequence selected from the group consistingof SEQ ID NOs: 8, 28, 48, 68, 88, 108, 128, 148, and 168, or an aminoacid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions as compared to SEQ ID NOs: 8, 28,48, 68, 88, 108, 128, 148, and 168; a VL CDR2 region having an aminoacid sequence selected from the group consisting of SEQ ID NOs: 9, 29,49, 69, 89, 109, 129, 149, and 169, or an amino acid sequence havingone, two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 9, 29, 49, 69, 89, 109, 129, 149,and 169; and a VL CDR3 region having an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 10, 30, 50, 70, 90, 110, 130,150, and 170, and 373, or an amino acid sequence having one, two, three,four or five amino acid substitutions, deletions or additions ascompared to SEQ ID NOs: 10, 30, 50, 70, 90, 110, 130, 150, and 170.

Accordingly, in another embodiment, the invention provides isolated HER3monoclonal antibodies, or fragment thereof bind to domains 3-4 of HER3,consisting of a heavy chain variable region having: a VH CDR1 regionconsisting of an amino acid sequence selected from the group having SEQID NOs: 182, 202, 222, 242, 262, 282, 302, 322, 342, 362, 382, 402, 422,442, 462, 482, 502, 522, 542, 562, 582, 602, 622, 642, 662, and 682 oran amino acid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions as compared to SEQ ID NOs: 182,202, 222, 242, 262, 282, 302, 322, 342, 362, 382, 402, 422, 442, 462,482, 502, 522, 542, 562, 582, 602, 622, 642, 662, and 682; a VH CDR2region having an amino acid sequence selected from the group consistingof SEQ ID NOs: 183, 203, 223, 243, 263, 283, 303, 323, 343, 363, 383,403, 423, 443, 463, 483, 503, 523, 543, 563, 583, 603, 623, 643, 663,and 683 or an amino acid sequence having one, two, three, four or fiveamino acid substitutions, deletions or additions as compared to SEQ IDNOs: 183, 203, 223, 243, 263, 283, 303, 323, 343, 363, 383, 403, 423,443, 463, 483, 503, 523, 543, 563, 583, 603, 623, 643, 663, and 683; aVH CDR3 region having an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304, 324, 344,364, 384, 404, 424, 444, 464, 484, 504, 524, 544, 564, 584, 604, 624,644, 664, and 684, or an amino acid sequence having one, two, three,four or five amino acid substitutions, deletions or additions ascompared to SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304, 324, 344,364, 384, 404, 424, 444, 464, 484, 504, 524, 544, 564, 584, 604, 624,644, 664, and 684; a VL CDR1 region having an amino acid sequenceselected from the group consisting of SEQ ID NOs: 188, 208, 228, 248,268, 288, 308, 328, 348, 368, 388, 408, 428, 448, 468, 488, 508, 528,548, 568, 588, 608, 628, 648, 668, and 688, or an amino acid sequencehaving one, two, three, four or five amino acid substitutions, deletionsor additions as compared to SEQ ID NOs: 188, 208, 228, 248, 268, 288,308, 328, 348, 368, 388, 408, 428, 448, 468, 488, 508, 528, 548, 568,588, 608, 628, 648, 668, and 688; a VL CDR2 region having an amino acidsequence selected from the group consisting of SEQ ID NOs: 189, 209,229, 249, 269, 289, 309, 329, 349, 369, 389, 409, 429, 449, 469, 489,509, 529, 549, 569, 589, 609, 629, 649, 669, and 689, or an amino acidsequence having one, two, three, four or five amino acid substitutions,deletions or additions as compared to SEQ ID NOs: 189, 209, 229, 249,269, 289, 309, 329, 349, 369, 389, 409, 429, 449, 469, 489, 509, 529,549, 569, 589, 609, 629, 649, 669, and 689; and a VL CDR3 region havingan amino acid sequence selected from the group consisting of SEQ ID NOs:190, 210, 230, 250, 270, 290, 310, 330, 350, 370, 390, 410, 430, 450,470, 490, 510, 530, 550, 570, 590, 610, 630, 650, 670, and 690, or anamino acid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions as compared to SEQ ID NOs: 190,210, 230, 250, 270, 290, 310, 330, 350, 370, 390, 410, 430, 450, 470,490, 510, 530, 550, 570, 590, 610, 630, 650, 670, and 690.

Grafting Antibody Fragments Into Alternative Frameworks or Scaffolds

A wide variety of antibody/immunoglobulin frameworks or scaffolds can beemployed so long as the resulting polypeptide includes at least onebinding region which specifically binds to HER3. Such frameworks orscaffolds include the 5 main idiotypes of human immunoglobulins, orfragments thereof, and include immunoglobulins of other animal species,preferably having humanized aspects. Novel frameworks, scaffolds andfragments continue to be discovered and developed by those skilled inthe art.

In one aspect, the invention pertains to generating non-immunoglobulinbased antibodies using non-immunoglobulin scaffolds onto which CDRs ofthe invention can be grafted. Known or future non-immunoglobulinframeworks and scaffolds may be employed, as long as they comprise abinding region specific for the target HER3 protein (e.g., human and/orcynomologus HER3). Known non-immunoglobulin frameworks or scaffoldsinclude, but are not limited to, fibronectin (Compound Therapeutics,Inc., Waltham, Mass.), ankyrin (Molecular Partners AG, Zurich,Switzerland), domain antibodies (Domantis, Ltd., Cambridge, Mass., andAblynx nv, Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG,Freising, Germany), small modular immuno-pharmaceuticals (TrubionPharmaceuticals Inc., Seattle, Wash.), maxybodies (Avidia, Inc.,Mountain View, Calif.), Protein A (Affibody AG, Sweden), and affilin(gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany).

The fibronectin scaffolds are based on fibronectin type III domain(e.g., the tenth module of the fibronectin type III (¹⁰ Fn3 domain)).The fibronectin type III domain has 7 or 8 beta strands which aredistributed between two beta sheets, which themselves pack against eachother to form the core of the protein, and further containing loops(analogous to CDRs) which connect the beta strands to each other and aresolvent exposed. There are at least three such loops at each edge of thebeta sheet sandwich, where the edge is the boundary of the proteinperpendicular to the direction of the beta strands (see U.S. Pat. No.6,818,418). These fibronectin-based scaffolds are not an immunoglobulin,although the overall fold is closely related to that of the smallestfunctional antibody fragment, the variable region of the heavy chain,which comprises the entire antigen recognition unit in camel and llamaIgG. Because of this structure, the non-immunoglobulin antibody mimicsantigen binding properties that are similar in nature and affinity tothose of antibodies. These scaffolds can be used in a loop randomizationand shuffling strategy in vitro that is similar to the process ofaffinity maturation of antibodies in vivo. These fibronectin-basedmolecules can be used as scaffolds where the loop regions of themolecule can be replaced with CDRs of the invention using standardcloning techniques.

The ankyrin technology is based on using proteins with ankyrin derivedrepeat modules as scaffolds for bearing variable regions which can beused for binding to different targets. The ankyrin repeat module is a 33amino acid polypeptide consisting of two anti-parallel α-helices and aβ-turn. Binding of the variable regions is mostly optimized by usingribosome display.

Avimers are derived from natural A-domain containing protein such asHER3. These domains are used by nature for protein-protein interactionsand in human over 250 proteins are structurally based on A-domains.Avimers consist of a number of different “A-domain” monomers (2-10)linked via amino acid linkers. Avimers can be created that can bind tothe target antigen using the methodology described in, for example, U.S.Patent Application Publication Nos. 20040175756; 20050053973;20050048512; and 20060008844.

Affibody affinity ligands are small, simple proteins composed of athree-helix bundle based on the scaffold of one of the IgG-bindingdomains of Protein A. Protein A is a surface protein from the bacteriumStaphylococcus aureus. This scaffold domain consists of 58 amino acids,13 of which are randomized to generate affibody libraries with a largenumber of ligand variants (See e.g., U.S. Pat. No. 5,831,012). Affibodymolecules mimic antibodies, they have a molecular weight of 6 kDa,compared to the molecular weight of antibodies, which is 150 kDa. Inspite of its small size, the binding site of affibody molecules issimilar to that of an antibody.

Anticalins are products developed by the company Pieris ProteoLab AG.They are derived from lipocalins, a widespread group of small and robustproteins that are usually involved in the physiological transport orstorage of chemically sensitive or insoluble compounds. Several naturallipocalins occur in human tissues or body liquids. The proteinarchitecture is reminiscent of immunoglobulins, with hypervariable loopson top of a rigid framework. However, in contrast with antibodies ortheir recombinant fragments, lipocalins are composed of a singlepolypeptide chain with 160 to 180 amino acid residues, being justmarginally bigger than a single immunoglobulin domain. The set of fourloops, which makes up the binding pocket, shows pronounced structuralplasticity and tolerates a variety of side chains. The binding site canthus be reshaped in a proprietary process in order to recognizeprescribed target molecules of different shape with high affinity andspecificity. One protein of lipocalin family, the bilin-binding protein(BBP) of Pieris Brassicae has been used to develop anticalins bymutagenizing the set of four loops. One example of a patent applicationdescribing anticalins is in PCT Publication No. WO 199916873.

Affilin molecules are small non-immunoglobulin proteins which aredesigned for specific affinities towards proteins and small molecules.New affilin molecules can be very quickly selected from two libraries,each of which is based on a different human derived scaffold protein.Affilin molecules do not show any structural homology to immunoglobulinproteins. Currently, two affilin scaffolds are employed, one of which isgamma crystalline, a human structural eye lens protein and the other is“ubiquitin” superfamily proteins. Both human scaffolds are very small,show high temperature stability and are almost resistant to pH changesand denaturing agents. This high stability is mainly due to the expandedbeta sheet structure of the proteins. Examples of gamma crystallinederived proteins are described in WO200104144 and examples of“ubiquitin-like” proteins are described in WO2004106368.

Protein epitope mimetics (PEM) are medium-sized, cyclic, peptide-likemolecules (MW 1-2 kDa) mimicking beta-hairpin secondary structures ofproteins, the major secondary structure involved in protein-proteininteractions.

In some embodiments, the Fabs are converted to silent IgG1 format bychanging the Fc region. For example, antibodies in Table 1 or Table 2can be converted to IgG format.

Human or Humanized Antibodies

The present invention provides fully human antibodies that specificallybind to a HER3 protein (e.g., human and/or cynomologus/mouse/rat HER3).Compared to the chimeric or humanized antibodies, the human HER3antibodies or fragments thereof, have further reduced antigenicity whenadministered to human subjects.

Human HER3 antibodies or fragments thereof can be generated usingmethods that are known in the art. For example, the humaneeringtechnology used to converting non-human antibodies into engineered humanantibodies. U.S. Patent Publication No. 20050008625 describes an in vivomethod for replacing a nonhuman antibody variable region with a humanvariable region in an antibody while maintaining the same or providingbetter binding characteristics relative to that of the nonhumanantibody. The method relies on epitope guided replacement of variableregions of a non-human reference antibody with a fully human antibody.The resulting human antibody is generally unrelated structurally to thereference nonhuman antibody, but binds to the same epitope on the sameantigen as the reference antibody. Briefly, the serial epitope-guidedcomplementarity replacement approach is enabled by setting up acompetition in cells between a “competitor” and a library of diversehybrids of the reference antibody (“test antibodies”) for binding tolimiting amounts of antigen in the presence of a reporter system whichresponds to the binding of test antibody to antigen. The competitor canbe the reference antibody or derivative thereof such as a single-chainFv fragment. The competitor can also be a natural or artificial ligandof the antigen which binds to the same epitope as the referenceantibody. The only requirements of the competitor are that it binds tothe same epitope as the reference antibody, and that it competes withthe reference antibody for antigen binding. The test antibodies have oneantigen-binding V-region in common from the nonhuman reference antibody,and the other V-region selected at random from a diverse source such asa repertoire library of human antibodies. The common V-region from thereference antibody serves as a guide, positioning the test antibodies onthe same epitope on the antigen, and in the same orientation, so thatselection is biased toward the highest antigen-binding fidelity to thereference antibody.

Many types of reporter system can be used to detect desired interactionsbetween test antibodies and antigen. For example, complementing reporterfragments may be linked to antigen and test antibody, respectively, sothat reporter activation by fragment complementation only occurs whenthe test antibody binds to the antigen. When the test antibody- andantigen-reporter fragment fusions are co-expressed with a competitor,reporter activation becomes dependent on the ability of the testantibody to compete with the competitor, which is proportional to theaffinity of the test antibody for the antigen. Other reporter systemsthat can be used include the reactivator of an auto-inhibited reporterreactivation system (RAIR) as disclosed in U.S. patent application Ser.No. 10/208,730 (Publication No. 20030198971), or competitive activationsystem disclosed in U.S. patent application Ser. No. 10/076,845(Publication No. 20030157579).

With the serial epitope-guided complementarity replacement system,selection is made to identify cells expresses a single test antibodyalong with the competitor, antigen, and reporter components. In thesecells, each test antibody competes one-on-one with the competitor forbinding to a limiting amount of antigen. Activity of the reporter isproportional to the amount of antigen bound to the test antibody, whichin turn is proportional to the affinity of the test antibody for theantigen and the stability of the test antibody. Test antibodies areinitially selected on the basis of their activity relative to that ofthe reference antibody when expressed as the test antibody. The resultof the first round of selection is a set of “hybrid” antibodies, each ofwhich is comprised of the same non-human V-region from the referenceantibody and a human V-region from the library, and each of which bindsto the same epitope on the antigen as the reference antibody. One ofmore of the hybrid antibodies selected in the first round will have anaffinity for the antigen comparable to or higher than that of thereference antibody.

In the second V-region replacement step, the human V-regions selected inthe first step are used as guide for the selection of human replacementsfor the remaining non-human reference antibody V-region with a diverselibrary of cognate human V-regions. The hybrid antibodies selected inthe first round may also be used as competitors for the second round ofselection. The result of the second round of selection is a set of fullyhuman antibodies which differ structurally from the reference antibody,but which compete with the reference antibody for binding to the sameantigen. Some of the selected human antibodies bind to the same epitopeon the same antigen as the reference antibody. Among these selectedhuman antibodies, one or more binds to the same epitope with an affinitywhich is comparable to or higher than that of the reference antibody.

Using one of the mouse or chimeric HER3 antibodies or fragments thereofdescribed above as the reference antibody, this method can be readilyemployed to generate human antibodies that bind to human HER3 with thesame binding specificity and the same or better binding affinity. Inaddition, such human HER3 antibodies or fragments thereof can also becommercially obtained from companies which customarily produce humanantibodies, e.g., KaloBios, Inc. (Mountain View, Calif.).

Camelid Antibodies

Antibody proteins obtained from members of the camel and dromedary(Camelus bactrianus and Calelus dromaderius) family including new worldmembers such as llama species (Lama paccos, Lama glama and Lama vicugna)have been characterized with respect to size, structural complexity andantigenicity for human subjects. Certain IgG antibodies from this familyof mammals as found in nature lack light chains, and are thusstructurally distinct from the typical four chain quaternary structurehaving two heavy and two light chains, for antibodies from otheranimals. See PCT/EP93/02214 (WO 94/04678 published 3 Mar. 1994).

A region of the camelid antibody which is the small single variabledomain identified as VHH can be obtained by genetic engineering to yielda small protein having high affinity for a target, resulting in a lowmolecular weight antibody-derived protein known as a “camelid nanobody”.See U.S. Pat. No. 5,759,808 issued Jun. 2, 1998; see also Stijlemans etal., (2004) J Biol Chem 279:1256-1261; Dumoulin et al., (2003) Nature424:783-788; Pleschberger et al., (2003) Bioconjugate Chem 14:440-448;Cortez-Retamozo et al., (2002) Int J Cancer 89:456-62; and Lauwereys etal., (1998) EMBO J. 17:3512-3520. Engineered libraries of camelidantibodies and antibody fragments are commercially available, forexample, from Ablynx, Ghent, Belgium. (e.g., US20060115470; Domantis(US20070065440, US20090148434). As with other antibodies of non-humanorigin, an amino acid sequence of a camelid antibody can be alteredrecombinantly to obtain a sequence that more closely resembles a humansequence, i.e., the nanobody can be “humanized”. Thus the natural lowantigenicity of camelid antibodies to humans can be further reduced.

The camelid nanobody has a molecular weight approximately one-tenth thatof a human IgG molecule, and the protein has a physical diameter of onlya few nanometers. One consequence of the small size is the ability ofcamelid nanobodies to bind to antigenic sites that are functionallyinvisible to larger antibody proteins, i.e., camelid nanobodies areuseful as reagents detect antigens that are otherwise cryptic usingclassical immunological techniques, and as possible therapeutic agents.Thus yet another consequence of small size is that a camelid nanobodycan inhibit as a result of binding to a specific site in a groove ornarrow cleft of a target protein, and hence can serve in a capacity thatmore closely resembles the function of a classical low molecular weightdrug than that of a classical antibody.

The low molecular weight and compact size further result in camelidnanobodies being extremely thermostable, stable to extreme pH and toproteolytic digestion, and poorly antigenic. Another consequence is thatcamelid nanobodies readily move from the circulatory system intotissues, and even cross the blood-brain barrier and can treat disordersthat affect nervous tissue. Nanobodies can further facilitated drugtransport across the blood brain barrier. See U.S. patent application20040161738 published Aug. 19, 2004. These features combined with thelow antigenicity to humans indicate great therapeutic potential.Further, these molecules can be fully expressed in prokaryotic cellssuch as E. coli and are expressed as fusion proteins with bacteriophageand are functional.

Accordingly, a feature of the present invention is a camelid antibody ornanobody having high affinity for HER3. In certain embodiments herein,the camelid antibody or nanobody is naturally produced in the camelidanimal, i.e., is produced by the camelid following immunization withHER3 or a peptide fragment thereof, using techniques described hereinfor other antibodies. Alternatively, the HER3-binding camelid nanobodyis engineered, i.e., produced by selection for example from a library ofphage displaying appropriately mutagenized camelid nanobody proteinsusing panning procedures with HER3 as a target as described in theexamples herein. Engineered nanobodies can further be customized bygenetic engineering to have a half life in a recipient subject of from45 minutes to two weeks. In a specific embodiment, the camelid antibodyor nanobody is obtained by grafting the CDRs sequences of the heavy orlight chain of the human antibodies of the invention into nanobody orsingle domain antibody framework sequences, as described for example inPCT/EP93/02214. In one embodiment, the camelid antibody or nanobodybinds to at least amino acids residue in domain 3 of HER3 selected fromamino acid residues: 335-342, 362-376, 398, 400, 424-428, 431, 433-434and 455 (within domain 3), or a subset thereof. In one embodiment, thecamelid antibody or nanobody binds to at least amino acids residue indomain 3 of HER3 selected from amino acid residues: 571, 582-584,596-597, 600-602, 609-615 (of domain 4), or a subset thereof.

Bispecific Molecules and Multivalent Antibodies

In another aspect, the present invention features biparatopic,bispecific or multispecific molecules comprising an antibody or afragment thereof that binds to a non-linear or conformational epitopewithin domain 3 of HER3. In another aspect, the biparatopic, bispecificor multispecific molecules comprise an antibody or a fragment thereofthat binds to an epitope within domain 4 of HER3. The antibody orfragment thereof can be derivatized or linked to another functionalmolecule, e.g., another peptide or protein (e.g., another antibody orligand for a receptor) to generate a bispecific molecule that binds toat least two different binding sites or target molecules. The antibodyor fragment thereof may in fact be derivatized or linked to more thanone other functional molecule to generate biparatopic or multi-specificmolecules that bind to more than two different binding sites and/ortarget molecules; such biparatopic or multi-specific molecules. Tocreate a bispecific molecule, an antibody or fragment thereof can befunctionally linked (e.g., by chemical coupling, genetic fusion,non-covalent association or otherwise) to one or more other bindingmolecules, such as another antibody, antibody fragment, peptide orbinding mimetic, such that a bispecific molecule results.

Further clinical benefits may be provided by the binding of two or moreantigens within one antibody (Coloma et al., (1997); Merchant et al.,(1998); Alt et al., (1999); Zuo et al., (2000); Lu et al., (2004); Lu etal., (2005); Marvin et al., (2005); Marvin et al., (2006); Shen et al.,(2007); Wu et al., (2007); Dimasi et al., (2009); Michaelson et al.,(2009)). (Morrison et al., (1997) Nature Biotech. 15:159-163; Alt et al.(1999) FEBS Letters 454:90-94; Zuo et al., (2000) Protein Engineering13:361-367; Lu et al., (2004) JBC 279:2856-2865; Lu et al., (2005) JBC280:19665-19672; Marvin et al., (2005) Acta Pharmacologica Sinica26:649-658; Marvin et al., (2006) Curr Opin Drug Disc Develop 9:184-193;Shen et al., (2007) J Immun Methods 218:65-74; Wu et al., (2007) Nat.Biotechnol. 11:1290-1297; Dimasi et al., (2009) J Mol. Biol.393:672-692; and Michaelson et al., (2009) mAbs 1:128-141.

The bispecific molecules can be prepared by conjugating the constituentbinding specificities, using methods known in the art. For example, eachbinding specificity of the bispecific molecule can be generatedseparately and then conjugated to one another, for example, a variety ofcoupling or cross-linking agents can be used for covalent conjugation.Examples of cross-linking agents include protein A, carbodiimide,N-succinimidyl-5-acetyl-thioacetate (SATA),5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide(oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), andsulfosuccinimidyl 4-(N-maleimidomethyl)cyclohaxane-1-carboxylate(sulfo-SMCC) (see e.g., Karpovsky et al., (1984) J. Exp. Med. 160:1686;Liu et al., (1985) Proc. Natl. Acad. Sci. USA 82:8648). Other methodsinclude those described in Paulus (1985) Behring Ins. Mitt. No.78:118-132; Brennan et al., (1985) Science 229:81-83), and Glennie etal., (1987) J. Immunol. 139: 2367-2375). Conjugating agents are SATA andsulfo-SMCC, both available from Pierce Chemical Co. (Rockford, Ill.).

With antibodies, they can be conjugated by sulfhydryl bonding of theC-terminus hinge regions of the two heavy chains. In a particularlyembodiment, the hinge region is modified to contain an odd number ofsulfhydryl residues, for example one, prior to conjugation.

Alternatively, both binding specificities can be encoded in the samevector and expressed and assembled in the same host cell. This method isparticularly useful where the bispecific molecule is a mAb×mAb, mAb×Fab,Fab×F(ab′)₂ or ligand x Fab fusion protein. A bispecific molecule of theinvention can be a single chain molecule comprising one single chainantibody and a binding determinant, or a single chain bispecificmolecule comprising two binding determinants. Bispecific molecules maycomprise at least two single chain molecules. Methods for preparingbispecific molecules are described for example in U.S. Pat. No.5,260,203; U.S. Pat. No. 5,455,030; U.S. Pat. No. 4,881,175; U.S. Pat.No. 5,132,405; U.S. Pat. No. 5,091,513; U.S. Pat. No. 5,476,786; U.S.Pat. No. 5,013,653; U.S. Pat. No. 5,258,498; and U.S. Pat. No.5,482,858.

Binding of the bispecific molecules to their specific targets can beconfirmed by, for example, enzyme-linked immunosorbent assay (ELISA),radioimmunoassay (REA), FACS analysis, bioassay (e.g., growthinhibition), or Western Blot assay. Each of these assays generallydetects the presence of protein-antibody complexes of particularinterest by employing a labeled reagent (e.g., an antibody) specific forthe complex of interest.

In another aspect, the present invention provides multivalent compoundscomprising at least two identical or different fragments of theantibodies binding to HER3. The antibody fragments can be linkedtogether via protein fusion or covalent or non covalent linkage.Tetravalent compounds can be obtained for example by cross-linkingantibodies of the antibodies of the invention with an antibody thatbinds to the constant regions of the antibodies of the invention, forexample the Fc or hinge region. Trimerizing domain are described forexample in Borean patent EP 1012280B1. Pentamerizing modules aredescribed for example in PCT/EP97/05897.

In one embodiment, the biparatopic/bispecific antibody binds to at leastamino acids residue in domain 3 of HER3 selected from amino acidresidues: 335-342, 362-376, 398, 400, 424-428, 431, 433-434 and 455(within domain 3), or a subset thereof. In one embodiment, thebiparatopic/bispecific antibody binds to at least amino acids residue indomain 3 of HER3 selected from amino acid residues: 571, 582-584,596-597, 600-602, 609-615 (of domain 4), or a subset thereof.

In another embodiment, the invention pertains to dual functionantibodies in which a single monoclonal antibody has been modified suchthat the antigen binding site binds to more than one antigen, such as adual function antibody which binds both HER3 and another antigen (e.g.,HER1, HER2, and HER4). In another embodiment, the invention pertains toa dual function antibody that targets antigens having the sameconformation, for example an antigen that has the same conformation ofHER3 in the “closed” or “inactive” state. Examples of antigens with thesame conformation of HER3 in the “closed” or “inactive” state include,but are not limited to, HER1 and HER4. Thus, a dual function antibodymay bind to both HER3 and HER1; HER3 and HER4, or HER1 and HER4. Thedual binding specificity of the dual function antibody may furthertranslate into dual activity, or inhibition of activity. (See e.g.,Jenny Bostrom et al., (2009) Science: 323; 1610-1614).

Antibodies with Extended Half Life

The present invention provides for antibodies or fragments thereof thatspecifically bind to a non-linear or conformational epitope withindomain 3 of HER3 which have an extended half-life in vivo. The presentinvention also provides for antibodies that specifically bind to anepitope within domain 4 of HER3 which have an extended half-life invivo.

Many factors may affect a protein's half life in vivo. For examples,kidney filtration, metabolism in the liver, degradation by proteolyticenzymes (proteases), and immunogenic responses (e.g., proteinneutralization by antibodies and uptake by macrophages and dentriticcells). A variety of strategies can be used to extend the half life ofthe antibodies of the present invention. For example, by chemicallinkage to polyethyleneglycol (PEG), reCODE PEG, antibody scaffold,polysialic acid (PSA), hydroxyethyl starch (HES), albumin-bindingligands, and carbohydrate shields; by genetic fusion to proteins bindingto serum proteins, such as albumin, IgG, FcRn, and transferring; bycoupling (genetically or chemically) to other binding moieties that bindto serum proteins, such as nanobodies, Fabs, DARPins, avimers,affibodies, and anticalins; by genetic fusion to rPEG, albumin, domainof albumin, albumin-binding proteins, and Fc; or by incorporation intonanocarriers, slow release formulations, or medical devices.

To prolong the serum circulation of antibodies in vivo, inert polymermolecules such as high molecular weight PEG can be attached to theantibodies or a fragment thereof with or without a multifunctionallinker either through site-specific conjugation of the PEG to the N- orC-terminus of the antibodies or via epsilon-amino groups present onlysine residues. To pegylate an antibody, the antibody, or fragmentthereof, typically is reacted with polyethylene glycol (PEG), such as areactive ester or aldehyde derivative of PEG, under conditions in whichone or more PEG groups become attached to the antibody or antibodyfragment. The pegylation can be carried out by an acylation reaction oran alkylation reaction with a reactive PEG molecule (or an analogousreactive water-soluble polymer). As used herein, the term “polyethyleneglycol” is intended to encompass any of the forms of PEG that have beenused to derivatize other proteins, such as mono (C1-C10) alkoxy- oraryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certainembodiments, the antibody to be pegylated is an aglycosylated antibody.Linear or branched polymer derivatization that results in minimal lossof biological activity will be used. The degree of conjugation can beclosely monitored by SDS-PAGE and mass spectrometry to ensure properconjugation of PEG molecules to the antibodies. Unreacted PEG can beseparated from antibody-PEG conjugates by size-exclusion or byion-exchange chromatography. PEG-derivatized antibodies can be testedfor binding activity as well as for in vivo efficacy using methodswell-known to those of skill in the art, for example, by immunoassaysdescribed herein. Methods for pegylating proteins are known in the artand can be applied to the antibodies of the invention. See for example,EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.

Other modified pegylation technologies include reconstituting chemicallyorthogonal directed engineering technology (ReCODE PEG), whichincorporates chemically specified side chains into biosynthetic proteinsvia a reconstituted system that includes tRNA synthetase and tRNA. Thistechnology enables incorporation of more than 30 new amino acids intobiosynthetic proteins in E. coli, yeast, and mammalian cells. The tRNAincorporates a normative amino acid any place an amber codon ispositioned, converting the amber from a stop codon to one that signalsincorporation of the chemically specified amino acid.

Recombinant pegylation technology (rPEG) can also be used for serumhalf-life extension. This technology involves genetically fusing a300-600 amino acid unstructured protein tail to an existingpharmaceutical protein. Because the apparent molecular weight of such anunstructured protein chain is about 15-fold larger than its actualmolecular weight, the serum half-life of the protein is greatlyincreased. In contrast to traditional PEGylation, which requireschemical conjugation and repurification, the manufacturing process isgreatly simplified and the product is homogeneous.

Polysialytion is another technology, which uses the natural polymerpolysialic acid (PSA) to prolong the active life and improve thestability of therapeutic peptides and proteins. PSA is a polymer ofsialic acid (a sugar). When used for protein and therapeutic peptidedrug delivery, polysialic acid provides a protective microenvironment onconjugation. This increases the active life of the therapeutic proteinin the circulation and prevents it from being recognized by the immunesystem. The PSA polymer is naturally found in the human body. It wasadopted by certain bacteria which evolved over millions of years to coattheir walls with it. These naturally polysialylated bacteria were thenable, by virtue of molecular mimicry, to foil the body's defense system.PSA, nature's ultimate stealth technology, can be easily produced fromsuch bacteria in large quantities and with predetermined physicalcharacteristics. Bacterial PSA is completely non-immunogenic, even whencoupled to proteins, as it is chemically identical to PSA in the humanbody.

Another technology include the use of hydroxyethyl starch (“HES”)derivatives linked to antibodies. HES is a modified natural polymerderived from waxy maize starch and can be metabolized by the body'senzymes. HES solutions are usually administered to substitute deficientblood volume and to improve the rheological properties of the blood.Hesylation of an antibody enables the prolongation of the circulationhalf-life by increasing the stability of the molecule, as well as byreducing renal clearance, resulting in an increased biological activity.By varying different parameters, such as the molecular weight of HES, awide range of HES antibody conjugates can be customized.

Antibodies having an increased half-life in vivo can also be generatedintroducing one or more amino acid modifications (i.e., substitutions,insertions or deletions) into an IgG constant domain, or FcRn bindingfragment thereof (preferably a Fc or hinge Fc domain fragment). See,e.g., International Publication No. WO 98/23289; InternationalPublication No. WO 97/34631; and U.S. Pat. No. 6,277,375.

Further, antibodies can be conjugated to albumin in order to make theantibody or antibody fragment more stable in vivo or have a longer halflife in vivo. The techniques are well-known in the art, see, e.g.,International Publication Nos. WO 93/15199, WO 93/15200, and WO01/77137; and European Patent No. EP 413,622.

The HER3 antibody or a fragment thereof may also be fused to one or morehuman serum albumin (HSA) polypeptides, or a portion thereof. HSA, aprotein of 585 amino acids in its mature form, is responsible for asignificant proportion of the osmotic pressure of serum and alsofunctions as a carrier of endogenous and exogenous ligands. The role ofalbumin as a carrier molecule and its inert nature are desirableproperties for use as a carrier and transporter of polypeptides in vivo.The use of albumin as a component of an albumin fusion protein as acarrier for various proteins has been suggested in WO 93/15199, WO93/15200, and EP 413 622. The use of N-terminal fragments of HSA forfusions to polypeptides has also been proposed (EP 399 666).Accordingly, by genetically or chemically fusing or conjugating theantibodies or fragments thereof to albumin, can stabilize or extend theshelf-life, and/or to retain the molecule's activity for extendedperiods of time in solution, in vitro and/or in vivo.

Fusion of albumin to another protein may be achieved by geneticmanipulation, such that the DNA coding for HSA, or a fragment thereof,is joined to the DNA coding for the protein. A suitable host is thentransformed or transfected with the fused nucleotide sequences, soarranged on a suitable plasmid as to express a fusion polypeptide. Theexpression may be effected in vitro from, for example, prokaryotic oreukaryotic cells, or in vivo e.g. from a transgenic organism. Additionalmethods pertaining to HSA fusions can be found, for example, in WO2001077137 and WO 200306007, incorporated herein by reference. In aspecific embodiment, the expression of the fusion protein is performedin mammalian cell lines, for example, CHO cell lines. Altereddifferential binding of an antibody to a receptor at low or high pHs isalso contemplated to be within the scope of the invention. For example,the affinity of an antibody may be modified such that it remains boundto it's receptor at a low pH, e.g., the low pH within a lyzozome, bymodifying the antibody to include additional amino acids such as ahistine in a CDR of the antibody (See e.g., Tomoyuki Igawa et al. (2010)Nature Biotechnology; 28, 1203-1207).

Antibody Conjugates

The present invention provides antibodies or fragments thereof thatspecifically bind to HER3 recombinantly fused or chemically conjugated(including both covalent and non-covalent conjugations) to aheterologous protein or polypeptide (or fragment thereof, preferably toa polypeptide of at least 10, at least 20, at least 30, at least 40, atleast 50, at least 60, at least 70, at least 80, at least 90 or at least100 amino acids) to generate fusion proteins. In particular, theinvention provides fusion proteins comprising an antibody fragmentdescribed herein (e.g., a Fab fragment, Fd fragment, Fv fragment, F(ab)₂fragment, a VH domain, a VH CDR, a VL domain or a VL CDR) and aheterologous protein, polypeptide, or peptide. Methods for fusing orconjugating proteins, polypeptides, or peptides to an antibody or anantibody fragment are known in the art. See, e.g., U.S. Pat. Nos.5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946;European Patent Nos. EP 307,434 and EP 367,166; InternationalPublication Nos. WO 96/04388 and WO 91/06570; Ashkenazi et al., (1991)Proc. Natl. Acad. Sci. USA 88:10535-10539; Zheng et al., (1995) J.Immunol. 154:5590-5600; and Vil et al., (1992) Proc. Natl. Acad. Sci.USA 89:11337-11341.

Additional fusion proteins may be generated through the techniques ofgene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling(collectively referred to as “DNA shuffling”). DNA shuffling may beemployed to alter the activities of antibodies of the invention orfragments thereof (e.g., antibodies or fragments thereof with higheraffinities and lower dissociation rates). See, generally, U.S. Pat. Nos.5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten etal., (1997) Curr. Opinion Biotechnol. 8:724-33; Harayama, (1998) TrendsBiotechnol. 16(2):76-82; Hansson et al., (1999) J. Mol. Biol.287:265-76; and Lorenzo and Blasco, (1998) Biotechniques 24(2):308-313(each of these patents and publications are hereby incorporated byreference in its entirety). Antibodies or fragments thereof, or theencoded antibodies or fragments thereof, may be altered by beingsubjected to random mutagenesis by error-prone PCR, random nucleotideinsertion or other methods prior to recombination. A polynucleotideencoding an antibody or fragment thereof that specifically binds to aHER3 protein may be recombined with one or more components, motifs,sections, parts, domains, fragments, etc. of one or more heterologousmolecules.

Moreover, the antibodies or fragments thereof can be fused to markersequences, such as a peptide to facilitate purification. In preferredembodiments, the marker amino acid sequence is a hexa-histidine peptide(SEQ ID NO: 702), such as the tag provided in a pQE vector (QIAGEN,Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, manyof which are commercially available. As described in Gentz et al.,(1989) Proc. Natl. Acad. Sci. USA 86:821-824, for instance,hexa-histidine (SEQ ID NO: 702) provides for convenient purification ofthe fusion protein. Other peptide tags useful for purification include,but are not limited to, the hemagglutinin (“HA”) tag, which correspondsto an epitope derived from the influenza hemagglutinin protein (Wilsonet al., (1984) Cell 37:767), and the “flag” tag.

In other embodiments, antibodies of the present invention or fragmentsthereof conjugated to a diagnostic or detectable agent. Such antibodiescan be useful for monitoring or prognosing the onset, development,progression and/or severity of a disease or disorder as part of aclinical testing procedure, such as determining the efficacy of aparticular therapy. Such diagnosis and detection can accomplished bycoupling the antibody to detectable substances including, but notlimited to, various enzymes, such as, but not limited to, horseradishperoxidase, alkaline phosphatase, beta-galactosidase, oracetylcholinesterase; prosthetic groups, such as, but not limited to,streptavidin/biotin and avidin/biotin; fluorescent materials, such as,but not limited to, umbelliferone, fluorescein, fluoresceinisothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; luminescent materials, such as, but notlimited to, luminol; bioluminescent materials, such as but not limitedto, luciferase, luciferin, and aequorin; radioactive materials, such as,but not limited to, iodine (¹³¹I, ¹²⁵I, ¹²³I, and ¹²¹I), carbon (¹⁴C),sulfur (³⁵S), tritium (³H), indium (¹¹⁵In, ¹¹³In, ¹¹²In, and ¹¹¹In),technetium (⁹⁹Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga), palladium(¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F), ¹⁵³Sm, ¹⁷⁷Lu,¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ¹⁹⁰Y, 47Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴² Pr,¹⁰⁵Rh, ⁹⁷Ru, ⁶⁸Ge, ⁵⁷Co, ⁶⁵Zn, ⁸⁵Sr, ³²P, ¹⁵³Gd, ¹⁶⁹Yb, ⁵¹Cr, ⁵⁴Mn,⁷⁵Se, ¹¹³Sn, and ¹¹⁷Tin; and positron emitting metals using variouspositron emission tomographies, and noradioactive paramagnetic metalions.

The present invention further encompasses uses of antibodies orfragments thereof conjugated to a therapeutic moiety. An antibody orfragment thereof may be conjugated to a therapeutic moiety such as acytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent ora radioactive metal ion, e.g., alpha-emitters. A cytotoxin or cytotoxicagent includes any agent that is detrimental to cells.

Further, an antibody or fragment thereof may be conjugated to atherapeutic moiety or drug moiety that modifies a given biologicalresponse. Therapeutic moieties or drug moieties are not to be construedas limited to classical chemical therapeutic agents. For example, thedrug moiety may be a protein, peptide, or polypeptide possessing adesired biological activity. Such proteins may include, for example, atoxin such as abrin, ricin A, pseudomonas exotoxin, cholera toxin, ordiphtheria toxin; a protein such as tumor necrosis factor, α-interferon,β-interferon, nerve growth factor, platelet derived growth factor,tissue plasminogen activator, an apoptotic agent, an anti-angiogenicagent; or, a biological response modifier such as, for example, alymphokine. In one embodiment, the HER3 antibody, or a fragment thereofis conjugated to a therapeutic moiety, such as a cytotoxin, a drug(e.g., an immunosuppressant) or a radiotoxin. Such conjugates arereferred to herein as “immunoconjugates”. Immunoconjugates that includeone or more cytotoxins are referred to as “immunotoxins.” A cytotoxin orcytotoxic agent includes any agent that is detrimental to (e.g., kills)cells. Examples include taxon, cytochalasin B, gramicidin D, ethidiumbromide, emetine, mitomycin, etoposide, tenoposide, vincristine,vinblastine, t. colchicin, doxorubicin, daunorubicin, dihydroxyanthracin dione, mitoxantrone, mithramycin, actinomycin D,1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine,propranolol, and puromycin and analogs or homologs thereof. Therapeuticagents also include, for example, antimetabolites (e.g., methotrexate,6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracildecarbazine), ablating agents (e.g., mechlorethamine, thioepachloraxnbucil, meiphalan, carmustine (BSNU) and lomustine (CCNU),cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycinC, and cis-dichlorodiamine platinum (II) (DDP) cisplatin, anthracyclines(e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics(e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, andanthramycin (AMC)), and anti-mitotic agents (e.g., vincristine andvinblastine). (See e.g., Seattle Genetics US20090304721).

Other examples of therapeutic cytotoxins that can be conjugated to anantibody or fragment thereof of the invention include duocarmycins,calicheamicins, maytansines and auristatins, and derivatives thereof. Anexample of a calicheamicin antibody conjugate is commercially available(Mylotarg™; Wyeth-Ayerst).

Cytoxins can be conjugated to antibodies or fragments thereof of theinvention using linker technology available in the art. Examples oflinker types that have been used to conjugate a cytotoxin to an antibodyinclude, but are not limited to, hydrazones, thioethers, esters,disulfides and peptide-containing linkers. A linker can be chosen thatis, for example, susceptible to cleavage by low pH within the lysosomalcompartment or susceptible to cleavage by proteases, such as proteasespreferentially expressed in tumor tissue such as cathepsins (e.g.,cathepsins B, C, D).

For further discussion of types of cytotoxins, linkers and methods forconjugating therapeutic agents to antibodies, see also Saito et al.,(2003) Adv. Drug Deliv. Rev. 55:199-215; Trail et al., (2003) CancerImmunol. Immunother. 52:328-337; Payne, (2003) Cancer Cell 3:207-212;Allen, (2002) Nat. Rev. Cancer 2:750-763; Pastan and Kreitman, (2002)Curr. Opin. Investig. Drugs 3:1089-1091; Senter and Springer, (2001)Adv. Drug Deliv. Rev. 53:247-264.

Antibodies or fragments thereof of the present invention also can beconjugated to a radioactive isotope to generate cytotoxicradiopharmaceuticals, also referred to as radioimmunoconjugates.Examples of radioactive isotopes that can be conjugated to antibodiesfor use diagnostically or therapeutically include, but are not limitedto, iodine¹¹¹, indium¹¹¹, yttrium⁹⁰, and lutetium¹⁷⁷. Method forpreparing radioimmunconjugates are established in the art. Examples ofradioimmunoconjugates are commercially available, including Zevalin™(DEC Pharmaceuticals) and Bexxar™ (Corixa Pharmaceuticals), and similarmethods can be used to prepare radioimmunoconjugates using theantibodies of the invention. In certain embodiments, the macrocyclicchelator is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid(DOTA) which can be attached to the antibody via a linker molecule. Suchlinker molecules are commonly known in the art and described in Denardoet al., (1998) Clin Cancer Res. 4(10):2483-90; Peterson et al., (1999)Bioconjug. Chem. 10(4):553-7; and Zimmerman et al., (1999) Nucl. Med.Biol. 26(8):943-50, each incorporated by reference in their entireties.

Techniques for conjugating therapeutic moieties to antibodies are wellknown, see, e.g., Amon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies 84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., (1982)Immunol. Rev. 62:119-58.

Antibodies may also be attached to solid supports, which areparticularly useful for immunoassays or purification of the targetantigen. Such solid supports include, but are not limited to, glass,cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride orpolypropylene.

Antibody Combinations

An another aspect, the invention pertains to HER3 antibodies, orfragments thereof of the invention used with other therapeutic agentssuch as another antibodies, small molecule inhibitors, mTOR inhibitorsor PI3Kinase inhibitors. Examples include, but are not limited to, thefollowing:

HER1 inhibitors: The HER3 antibodies or fragments thereof can be usedwith HER1 inhibitors which include, but are not limited to, Matuzumab(EMD72000), Erbitux®/Cetuximab (Imclone), Vectibix®/Panitumumab (Amgen),mAb 806, and Nimotuzumab (TheraCIM), Iressa®/Gefitinib (Astrazeneca);CI-1033 (PD183805) (Pfizer), Lapatinib (GW-572016) (GlaxoSmithKline),Tykerb®/Lapatinib Ditosylate (SmithKlineBeecham), Tarceva®/Erlotinib HCL(OSI-774) (OSI Pharma), and PKI-166 (Novartis), andN-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3“S”)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide,sold under the tradename Tovok® by Boehringer Ingelheim).

HER2 inhibitors: The HER3 antibodies or fragments thereof can be usedwith HER2 inhibitors which include, but are not limited to, Pertuzumab(sold under the trademark Omnitarg®, by Genentech), Trastuzumab (soldunder the trademark Herceptin® by Genentech/Roche), MM-111, neratinib(also known as HKI-272,(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide,and described PCT Publication No. WO 05/028443), lapatinib or lapatinibditosylate (sold under the trademark Tykerb® by GlaxoSmithKline.

HER3 inhibitors: The HER3 antibodies or fragments thereof can be usedwith HER3 inhibitors which include, but are not limited to, MM-121,MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo),MEHD7945A (Genentech), and small molecules that inhibit HER3.

HER4 inhibitors: The HER3 antibodies or fragments thereof can be usedwith HER4 inhibitors.

PI3K inhibitors: The HER3 antibodies or fragments thereof can be usedwith PI3 kinase inhibitors which include, but are not limited to,4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine(also known as GDC 0941 and described in PCT Publication Nos. WO09/036,082 and WO 09/055,730),2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile(also known as BEZ 235 or NVP-BEZ 235, and described in PCT PublicationNo. WO 06/122806), BKM120 and BYL719.

mTOR inhibitors: The HER3 antibodies or fragments thereof can be usedwith mTOR inhibitors which include, but are not limited to, Temsirolimus(sold under the tradename Torisel® by Pfizer), ridaforolimus (formallyknown as deferolimus,(1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as Deforolimus, AP23573 and MK8669(Ariad Pharm.), and described in PCT Publication No. WO 03/064383),everolimus (RAD001) (sold under the tradename Afinitor® by Novartis),One or more therapeutic agents may be administered either simultaneouslyor before or after administration of a HER3 antibody or fragment thereofof the present invention.

Methods of Producing Antibodies of the Invention (i) Nucleic AcidsEncoding the Antibodies

The invention provides substantially purified nucleic acid moleculeswhich encode polypeptides comprising segments or domains of the HER3antibody chains described above.

Some of the nucleic acids of the invention comprise the nucleotidesequence encoding the HER3 antibody heavy chain variable region, and/orthe nucleotide sequence encoding the light chain variable region. In aspecific embodiment, the nucleic acid molecules are those identified inTable 1 or Table 2. Some other nucleic acid molecules of the inventioncomprise nucleotide sequences that are substantially identical (e.g., atleast 80%, 90%, 95%, 96%, 97%, 98%, or 99%) to the nucleotide sequencesof those identified in Table 1 or Table 2. When expressed fromappropriate expression vectors, polypeptides encoded by thesepolynucleotides are capable of exhibiting HER3 antigen binding capacity.

Also provided in the invention are polynucleotides which encode at leastone CDR region and usually all three CDR regions from the heavy or lightchain of the antibody or fragment thereof set forth above. Some otherpolynucleotides encode all or substantially all of the variable regionsequence of the heavy chain and/or the light chain of the antibody orfragment thereof set forth above. Because of the degeneracy of the code,a variety of nucleic acid sequences will encode each of theimmunoglobulin amino acid sequences.

The nucleic acid molecules of the invention can encode both a variableregion and a constant region of the antibody. Some of nucleic acidsequences of the invention comprise nucleotides encoding a mature heavychain variable region sequence that is substantially identical (e.g., atleast 80%, 90%, 95%, 96%, 97%, 98%, or 99%) to the mature heavy chainvariable region sequence of a HER3 antibody set forth in Table 1 orTable 2. Some other nucleic acid sequences comprising nucleotideencoding a mature light chain variable region sequence that issubstantially identical (e.g., at least 80%, 90%, 95%, 96%, 97%, 98%, or99%) to the mature light chain variable region sequence of a HER3antibody set forth in Table 1 or Table 2.

The polynucleotide sequences can be produced by de novo solid-phase DNAsynthesis or by PCR mutagenesis of an existing sequence encoding theantibody or fragment thereof. Direct chemical synthesis of nucleic acidscan be accomplished by methods known in the art, such as thephosphotriester method of Narang et al., (1979) Meth. Enzymol. 68:90;the phosphodiester method of Brown et al., (1979) Meth. Enzymol. 68:109;the diethylphosphoramidite method of Beaucage et al., (1981) Tetra.Lett., 22:1859; and the solid support method of U.S. Pat. No. 4,458,066.Introducing mutations to a polynucleotide sequence by PCR can beperformed as described in, e.g., PCR Technology: Principles andApplications for DNA Amplification, H. A. Erlich (Ed.), Freeman Press,NY, N.Y., 1992; PCR Protocols: A Guide to Methods and Applications,Innis et al. (Ed.), Academic Press, San Diego, Calif., 1990; Mattila etal., (1991) Nucleic Acids Res. 19:967; and Eckert et al., (1991) PCRMethods and Applications 1:17.

Also provided in the invention are expression vectors and host cells forproducing the antibodies or fragments thereof. Various expressionvectors can be employed to express the polynucleotides encoding the HER3antibody chains or fragments thereof. Both viral-based and nonviralexpression vectors can be used to produce the antibodies in a mammalianhost cell. Nonviral vectors and systems include plasmids, episomalvectors, typically with an expression cassette for expressing a proteinor RNA, and human artificial chromosomes (see, e.g., Harrington et al.,(1997) Nat Genet. 15:345). For example, nonviral vectors useful forexpression of the HER3 polynucleotides and polypeptides in mammalian(e.g., human) cells include pThioHis A, B & C, pcDNA3.1/His, pEBVHis A,B & C, (Invitrogen, San Diego, Calif.), MPSV vectors, and numerous othervectors known in the art for expressing other proteins. Useful viralvectors include vectors based on retroviruses, adenoviruses,adenoassociated viruses, herpes viruses, vectors based on SV40,papilloma virus, HBP Epstein Barr virus, vaccinia virus vectors andSemliki Forest virus (SFV). See, Brent et al., (1995) supra; Smith,Annu. Rev. Microbiol. 49:807; and Rosenfeld et al., (1992) Cell 68:143.

The choice of expression vector depends on the intended host cells inwhich the vector is to be expressed. Typically, the expression vectorscontain a promoter and other regulatory sequences (e.g., enhancers) thatare operably linked to the polynucleotides encoding an antibody chain orfragment thereof. In some embodiments, an inducible promoter is employedto prevent expression of inserted sequences except under inducingconditions. Inducible promoters include, e.g., arabinose, lacZ,metallothionein promoter or a heat shock promoter. Cultures oftransformed organisms can be expanded under noninducing conditionswithout biasing the population for coding sequences whose expressionproducts are better tolerated by the host cells. In addition topromoters, other regulatory elements may also be required or desired forefficient expression of antibody chain or fragment thereof. Theseelements typically include an ATG initiation codon and adjacent ribosomebinding site or other sequences. In addition, the efficiency ofexpression may be enhanced by the inclusion of enhancers appropriate tothe cell system in use (see, e.g., Scharf et al., (1994) Results Probl.Cell Differ. 20:125; and Bittner et al., (1987) Meth. Enzymol.,153:516). For example, the SV40 enhancer or CMV enhancer may be used toincrease expression in mammalian host cells.

The expression vectors may also provide a secretion signal sequenceposition to form a fusion protein with polypeptides encoded by insertedantibody or fragment sequences. More often, the inserted antibody orfragment sequences are linked to a signal sequences before inclusion inthe vector. Vectors to be used to receive sequences encoding theantibody or fragment light and heavy chain variable domains sometimesalso encode constant regions or parts thereof. Such vectors allowexpression of the variable regions as fusion proteins with the constantregions thereby leading to production of intact antibodies or fragmentsthereof. Typically, such constant regions are human.

The host cells for harboring and expressing the antibody or fragmentchains can be either prokaryotic or eukaryotic. E. coli is oneprokaryotic host useful for cloning and expressing the polynucleotidesof the present invention. Other microbial hosts suitable for use includebacilli, such as Bacillus subtilis, and other enterobacteriaceae, suchas Salmonella, Serratia, and various Pseudomonas species. In theseprokaryotic hosts, one can also make expression vectors, which typicallycontain expression control sequences compatible with the host cell(e.g., an origin of replication). In addition, any number of a varietyof well-known promoters will be present, such as the lactose promotersystem, a tryptophan (trp) promoter system, a beta-lactamase promotersystem, or a promoter system from phage lambda. The promoters typicallycontrol expression, optionally with an operator sequence, and haveribosome binding site sequences and the like, for initiating andcompleting transcription and translation. Other microbes, such as yeast,can also be employed to express antibodies or fragments thereof. Insectcells in combination with baculovirus vectors can also be used.

In some preferred embodiments, mammalian host cells are used to expressand produce the antibodies or fragments thereof. For example, they canbe either a hybridoma cell line expressing endogenous immunoglobulingenes or a mammalian cell line harboring an exogenous expression vector.These include any normal mortal or normal or abnormal immortal animal orhuman cell. For example, a number of suitable host cell lines capable ofsecreting intact immunoglobulins have been developed including the CHOcell lines, various Cos cell lines, HeLa cells, myeloma cell lines,transformed B-cells and hybridomas. The use of mammalian tissue cellculture to express polypeptides is discussed generally in, e.g.,Winnacker, FROM GENES TO CLONES, VCH Publishers, N.Y., N.Y., 1987.Expression vectors for mammalian host cells can include expressioncontrol sequences, such as an origin of replication, a promoter, and anenhancer (see, e.g., Queen et al., (1986) Immunol. Rev. 89:49-68), andnecessary processing information sites, such as ribosome binding sites,RNA splice sites, polyadenylation sites, and transcriptional terminatorsequences. These expression vectors usually contain promoters derivedfrom mammalian genes or from mammalian viruses. Suitable promoters maybe constitutive, cell type-specific, stage-specific, and/or modulatableor regulatable. Useful promoters include, but are not limited to, themetallothionein promoter, the constitutive adenovirus major latepromoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter,the MRP polIII promoter, the constitutive MPSV promoter, thetetracycline-inducible CMV promoter (such as the human immediate-earlyCMV promoter), the constitutive CMV promoter, and promoter-enhancercombinations known in the art.

Methods for introducing expression vectors containing the polynucleotidesequences of interest vary depending on the type of cellular host. Forexample, calcium chloride transfection is commonly utilized forprokaryotic cells, whereas calcium phosphate treatment orelectroporation may be used for other cellular hosts. (See generallySambrook, et al., supra). Other methods include, e.g., electroporation,calcium phosphate treatment, liposome-mediated transformation, injectionand microinjection, ballistic methods, virosomes, immunoliposomes,polycation:nucleic acid conjugates, naked DNA, artificial virions,fusion to the herpes virus structural protein VP22 (Elliot and O'Hare,(1997) Cell 88:223), agent-enhanced uptake of DNA, and ex vivotransduction. For long-term, high-yield production of recombinantproteins, stable expression will often be desired. For example, celllines which stably express antibody chains or fragments can be preparedusing expression vectors of the invention which contain viral origins ofreplication or endogenous expression elements and a selectable markergene. Following the introduction of the vector, cells may be allowed togrow for 1-2 days in an enriched media before they are switched toselective media. The purpose of the selectable marker is to conferresistance to selection, and its presence allows growth of cells whichsuccessfully express the introduced sequences in selective media.Resistant, stably transfected cells can be proliferated using tissueculture techniques appropriate to the cell type.

(ii) Generation of Monoclonal Antibodies of the Invention

Monoclonal antibodies (mAbs) can be produced by a variety of techniques,including conventional monoclonal antibody methodology e.g., thestandard somatic cell hybridization technique of Kohler and Milstein,(1975) Nature 256:495. Many techniques for producing monoclonal antibodycan be employed e.g., viral or oncogenic transformation of Blymphocytes.

An animal system for preparing hybridomas is the murine system.Hybridoma production in the mouse is a well established procedure.Immunization protocols and techniques for isolation of immunizedsplenocytes for fusion are known in the art. Fusion partners (e.g.,murine myeloma cells) and fusion procedures are also known.

Chimeric or humanized antibodies of the present invention can beprepared based on the sequence of a murine monoclonal antibody preparedas described above. DNA encoding the heavy and light chainimmunoglobulins can be obtained from the murine hybridoma of interestand engineered to contain non-murine (e.g., human) immunoglobulinsequences using standard molecular biology techniques. For example, tocreate a chimeric antibody, the murine variable regions can be linked tohuman constant regions using methods known in the art (see e.g., U.S.Pat. No. 4,816,567 to Cabilly et al.). To create a humanized antibody,the murine CDR regions can be inserted into a human framework usingmethods known in the art. See e.g., U.S. Pat. No. 5,225,539 to Winter,and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6180370 to Queenet al.

In a certain embodiment, the antibodies of the invention are humanmonoclonal antibodies. Such human monoclonal antibodies directed againstHER3 can be generated using transgenic or transchromosomic mice carryingparts of the human immune system rather than the mouse system. Thesetransgenic and transchromosomic mice include mice referred to herein asHuMAb mice and KM mice, respectively, and are collectively referred toherein as “human Ig mice.”

The HuMAb Mouse® (Medarex, Inc.) contains human immunoglobulin geneminiloci that encode un-rearranged human heavy (μ and γ) and κ lightchain immunoglobulin sequences, together with targeted mutations thatinactivate the endogenous μ and κ chain loci (see e.g., Lonberg et al.,(1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit reducedexpression of mouse IgM or κ, and in response to immunization, theintroduced human heavy and light chain transgenes undergo classswitching and somatic mutation to generate high affinity human IgGκmonoclonal (Lonberg et al., (1994) supra; reviewed in Lonberg, (1994)Handbook of Experimental Pharmacology 113:49-101; Lonberg and Huszar,(1995) Intern. Rev. Immunol. 13:65-93, and Harding and Lonberg, (1995)Ann. N.Y. Acad. Sci. 764:536-546). The preparation and use of HuMAbmice, and the genomic modifications carried by such mice, is furtherdescribed in Taylor et al., (1992) Nucleic Acids Research 20:6287-6295;Chen et al., (1993) International Immunology 5:647-656; Tuaillon et al.,(1993) Proc. Natl. Acad. Sci. USA 94:3720-3724; Choi et al., (1993)Nature Genetics 4:117-123; Chen et al., (1993) EMBO J. 12:821-830;Tuaillon et al., (1994) J. Immunol. 152:2912-2920; Taylor et al., (1994)International Immunology 579-591; and Fishwild et al., (1996) NatureBiotechnology 14:845-851, the contents of all of which are herebyspecifically incorporated by reference in their entirety. See further,U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650;5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; all toLonberg and Kay; U.S. Pat. No. 5,545,807 to Surani et al.; PCTPublication Nos. WO 92103918, WO 93/12227, WO 94/25585, WO 97113852, WO98/24884 and WO 99/45962, all to Lonberg and Kay; and PCT PublicationNo. WO 01/14424 to Korman et al.

In another embodiment, human antibodies of the invention can be raisedusing a mouse that carries human immunoglobulin sequences on transgenesand transchomosomes such as a mouse that carries a human heavy chaintransgene and a human light chain transchromosome. Such mice, referredto herein as “KM mice”, are described in detail in PCT Publication WO02/43478 to Ishida et al.

Still further, alternative transgenic animal systems expressing humanimmunoglobulin genes are available in the art and can be used to raiseHER3 antibodies of the invention. For example, an alternative transgenicsystem referred to as the Xenomouse (Abgenix, Inc.) can be used. Suchmice are described in, e.g., U.S. Pat. Nos. 5,939,598; 6,075,181;6,114,598; 6,150,584 and 6,162,963 to Kucherlapati et al.

Moreover, alternative transchromosomic animal systems expressing humanimmunoglobulin genes are available in the art and can be used to raiseHER3 antibodies of the invention. For example, mice carrying both ahuman heavy chain transchromosome and a human light chaintranchromosome, referred to as “TC mice” can be used; such mice aredescribed in Tomizuka et al., (2000) Proc. Natl. Acad. Sci. USA97:722-727. Furthermore, cows carrying human heavy and light chaintranschromosomes have been described in the art (Kuroiwa et al., (2002)Nature Biotechnology 20:889-894) and can be used to raise HER3antibodies of the invention.

Human monoclonal antibodies of the invention can also be prepared usingphage display methods for screening libraries of human immunoglobulingenes. Such phage display methods for isolating human antibodies areestablished in the art or described in the examples below. See forexample: U.S. Pat. Nos. 5,223,409; 5,403,484; and 5,571,698 to Ladner etal.; U.S. Pat. Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Pat.Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Pat. Nos.5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081 toGriffiths et al.

Human monoclonal antibodies of the invention can also be prepared usingSCID mice into which human immune cells have been reconstituted suchthat a human antibody response can be generated upon immunization. Suchmice are described in, for example, U.S. Pat. Nos. 5,476,996 and5,698,767 to Wilson et al.

(Iii) Framework or Fc Engineering

Engineered antibodies of the invention include those in whichmodifications have been made to framework residues within VH and/or VL,e.g. to improve the properties of the antibody. Typically such frameworkmodifications are made to decrease the immunogenicity of the antibody.For example, one approach is to “backmutate” one or more frameworkresidues to the corresponding germline sequence. More specifically, anantibody that has undergone somatic mutation may contain frameworkresidues that differ from the germline sequence from which the antibodyis derived. Such residues can be identified by comparing the antibodyframework sequences to the germline sequences from which the antibody isderived. To return the framework region sequences to their germlineconfiguration, the somatic mutations can be “backmutated” to thegermline sequence by, for example, site-directed mutagenesis. Such“backmutated” antibodies are also intended to be encompassed by theinvention.

Another type of framework modification involves mutating one or moreresidues within the framework region, or even within one or more CDRregions, to remove T cell-epitopes to thereby reduce the potentialimmunogenicity of the antibody. This approach is also referred to as“deimmunization” and is described in further detail in U.S. PatentPublication No. 20030153043 by Carr et al.

In addition or alternative to modifications made within the framework orCDR regions, antibodies of the invention may be engineered to includemodifications within the Fc region, typically to alter one or morefunctional properties of the antibody, such as serum half-life,complement fixation, Fc receptor binding, and/or antigen-dependentcellular cytotoxicity.

Furthermore, an antibody of the invention may be chemically modified(e.g., one or more chemical moieties can be attached to the antibody) orbe modified to alter its glycosylation, again to alter one or morefunctional properties of the antibody. Each of these embodiments isdescribed in further detail below. The numbering of residues in the Fcregion is that of the EU index of Kabat.

In one embodiment, the hinge region of CH1 is modified such that thenumber of cysteine residues in the hinge region is altered, e.g.,increased or decreased. This approach is described further in U.S. Pat.No. 5,677,425 by Bodmer et al. The number of cysteine residues in thehinge region of CH1 is altered to, for example, facilitate assembly ofthe light and heavy chains or to increase or decrease the stability ofthe antibody.

In another embodiment, the Fc hinge region of an antibody is mutated todecrease the biological half-life of the antibody. More specifically,one or more amino acid mutations are introduced into the CH2-CH3 domaininterface region of the Fc-hinge fragment such that the antibody hasimpaired Staphylococcyl protein A (SpA) binding relative to nativeFc-hinge domain SpA binding. This approach is described in furtherdetail in U.S. Pat. No. 6,165,745 by Ward et al.

In yet other embodiments, the Fc region is altered by replacing at leastone amino acid residue with a different amino acid residue to alter theeffector functions of the antibody. For example, one or more amino acidscan be replaced with a different amino acid residue such that theantibody has an altered affinity for an effector ligand but retains theantigen-binding ability of the parent antibody. The effector ligand towhich affinity is altered can be, for example, an Fc receptor or the Clcomponent of complement. This approach is described in further detail inU.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.

In another embodiment, one or more amino acids selected from amino acidresidues can be replaced with a different amino acid residue such thatthe antibody has altered C1q binding and/or reduced or abolishedcomplement dependent cytotoxicity (CDC). This approach is described infurther detail in U.S. Pat. No. 6,194,551 by Idusogie et al.

In another embodiment, one or more amino acid residues are altered tothereby alter the ability of the antibody to fix complement. Thisapproach is described further in PCT Publication WO 94/29351 by Bodmeret al.

In yet another embodiment, the Fc region is modified to increase theability of the antibody to mediate antibody dependent cellularcytotoxicity (ADCC) and/or to increase the affinity of the antibody foran Fcγ receptor by modifying one or more amino acids. This approach isdescribed further in PCT Publication WO 00/42072 by Presta. Moreover,the binding sites on human IgG1 for FcγR1, FcγRII, FcγRIII and FcRn havebeen mapped and variants with improved binding have been described (seeShields et al., (2001) J. Biol. Chen. 276:6591-6604).

In still another embodiment, the glycosylation of an antibody ismodified. For example, an aglycoslated antibody can be made (i.e., theantibody lacks glycosylation). Glycosylation can be altered to, forexample, increase the affinity of the antibody for “antigen”. Suchcarbohydrate modifications can be accomplished by, for example, alteringone or more sites of glycosylation within the antibody sequence. Forexample, one or more amino acid substitutions can be made that result inelimination of one or more variable region framework glycosylation sitesto thereby eliminate glycosylation at that site. Such aglycosylation mayincrease the affinity of the antibody for antigen. Such an approach isdescribed in further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861 byCo et al.

Additionally or alternatively, an antibody can be made that has analtered type of glycosylation, such as a hypofucosylated antibody havingreduced amounts of fucosyl residues or an antibody having increasedbisecting GlcNac structures. Such altered glycosylation patterns havebeen demonstrated to increase the ADCC ability of antibodies. Suchcarbohydrate modifications can be accomplished by, for example,expressing the antibody in a host cell with altered glycosylationmachinery. Cells with altered glycosylation machinery have beendescribed in the art and can be used as host cells in which to expressrecombinant antibodies of the invention to thereby produce an antibodywith altered glycosylation. For example, EP 1,176,195 by Hang et al.describes a cell line with a functionally disrupted FUT8 gene, whichencodes a fucosyl transferase, such that antibodies expressed in such acell line exhibit hypofucosylation. PCT Publication WO 03/035835 byPresta describes a variant CHO cell line, Lec13 cells, with reducedability to attach fucose to Asn(297)-linked carbohydrates, alsoresulting in hypofucosylation of antibodies expressed in that host cell(see also Shields et al., (2002) J. Biol. Chem. 277:26733-26740). PCTPublication WO 99/54342 by Umana et al. describes cell lines engineeredto express glycoprotein-modifying glycosyl transferases (e.g.,beta(1,4)—N acetylglucosaminyltransferase III (GnTIII)) such thatantibodies expressed in the engineered cell lines exhibit increasedbisecting GlcNac structures which results in increased ADCC activity ofthe antibodies (see also Umana et al., (1999) Nat. Biotech. 17:176-180).

In another embodiment, the antibody is modified to increase itsbiological half-life. Various approaches are possible. For example, oneor more of the following mutations can be introduced: T252L, T254S,T256F, as described in U.S. Pat. No. 6,277,375 to Ward. Alternatively,to increase the biological half life, the antibody can be altered withinthe CH1 or CL region to contain a salvage receptor binding epitope takenfrom two loops of a CH2 domain of an Fc region of an IgG, as describedin U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al.

(iv) Methods of Engineering Altered Antibodies

The HER3 antibodies or fragments thereof of the invention having VH andVL sequences or full length heavy and light chain sequences shown hereincan be used to create new HER3 antibodies by modifying full length heavychain and/or light chain sequences, VH and/or VL sequences, or theconstant region(s) attached thereto. Thus, in another aspect of theinvention, the structural features of a HER3 antibody or fragmentthereof are used to create structurally related HER3 antibodies thatretain at least one functional property of the antibodies of theinvention, such as binding to human HER3 and also inhibiting one or morefunctional properties of HER3. For example, one or more CDR regions ofthe antibodies of the present invention, or mutations thereof, can becombined recombinantly with known framework regions and/or other CDRs tocreate additional, recombinantly-engineered, HER3 antibodies asdiscussed above. Other types of modifications include those described inthe previous section. The starting material for the engineering methodis one or more of the VH and/or VL sequences provided herein, or one ormore CDR regions thereof. To create the engineered antibody, it is notnecessary to actually prepare (i.e., express as a protein) an antibodyhaving one or more of the VH and/or VL sequences provided herein, or oneor more CDR regions thereof. Rather, the information contained in thesequence(s) is used as the starting material to create a “secondgeneration” sequence(s) derived from the original sequence(s) and thenthe “second generation” sequence(s) is prepared and expressed as aprotein.

Accordingly, in another embodiment, the invention provides a method forpreparing a antibody that binds to domain 3 of HER3 consisting of: aheavy chain variable region antibody sequence having a CDR1 sequenceselected from the group consisting of SEQ ID NOs: 2, 22, 42, 62, 82,102, 122, 142, and 162; a CDR2 sequence selected from the groupconsisting of SEQ ID NOs: 3, 23, 43, 63, 83, 103, 123, 143, and 163;and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:4, 24, 44, 64, 84, 104, 124, 144, and 164; and a light chain variableregion antibody sequence having a CDR1 sequence selected from the groupconsisting of SEQ ID NOs: 8, 28, 48, 68, 88, 108, 128, 148, and 168; aCDR2 sequence selected from the group consisting of SEQ ID NOs: 9, 29,49, 69, 89, 109, 129, 149, and 169; and/or a CDR3 sequence selected fromthe group consisting of SEQ ID NOs: 10, 30, 50, 70, 90, 110, 130, 150,and 170; altering at least one amino acid residue within the heavy chainvariable region antibody sequence and/or the light chain variable regionantibody sequence to create at least one altered antibody sequence; andexpressing the altered antibody sequence as a protein. The alteredantibody sequence can also be prepared by screening antibody librarieshaving fixed CDR3 sequences or minimal essential binding determinants asdescribed in US20050255552 and diversity on CDR1 and CDR2 sequences. Thescreening can be performed according to any screening technologyappropriate for screening antibodies from antibody libraries, such asphage display technology.

Accordingly, in another embodiment, the invention provides a method forpreparing a antibody that binds to domains 3-4 of HER3 consisting of: aheavy chain variable region antibody sequence having a CDR1 sequenceselected from the group consisting of SEQ ID NOs: 182, 202, 222, 242,262, 282, 302, 322, 342, 362, 382, 402, 422, 442, 462, 482, 502, 522,542, 562, 582, 602, 622, 642, 662, and 682; a CDR2 sequence selectedfrom the group consisting of SEQ ID NOs: 183, 203, 223, 243, 263, 283,303, 323, 343, 363, 383, 403, 423, 443, 463, 483, 503, 523, 543, 563,583, 603, 623, 643, 663, and 683; and/or a CDR3 sequence selected fromthe group consisting of SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304,324, 344, 364, 384, 404, 424, 444, 464, 484, 504, 524, 544, 564, 584,604, 624, 644, 664, and 684; and a light chain variable region antibodysequence having a CDR1 sequence selected from the group consisting ofSEQ ID NOs: 188, 208, 228, 248, 268, 288, 308, 328, 348, 368, 388, 408,428, 448, 468, 488, 508, 528, 548, 568, 588, 608, 628, 648, 668, and688; a CDR2 sequence selected from the group consisting of SEQ ID NOs:189, 209, 229, 249, 269, 289, 309, 329, 349, 369, 389, 409, 429, 449,469, 489, 509, 529, 549, 569, 589, 609, 629, 649, 669, and 689; and/or aCDR3 sequence selected from the group consisting of SEQ ID NOs: 190,210, 230, 250, 270, 290, 310, 330, 350, 370, 390, 410, 430, 450, 470,490, 510, 530, 550, 570, 590, 610, 630, 650, 670, and 690; altering atleast one amino acid residue within the heavy chain variable regionantibody sequence and/or the light chain variable region antibodysequence to create at least one altered antibody sequence; andexpressing the altered antibody sequence as a protein. The alteredantibody sequence can also be prepared by screening antibody librarieshaving fixed CDR3 sequences or minimal essential binding determinants asdescribed in US20050255552 and diversity on CDR1 and CDR2 sequences. Thescreening can be performed according to any screening technologyappropriate for screening antibodies from antibody libraries, such asphage display technology.

Standard molecular biology techniques can be used to prepare and expressthe altered antibody sequence. The antibody encoded by the alteredantibody sequence(s) is one that retains one, some or all of thefunctional properties of the antibodies or fragments thereof describedherein, which functional properties include, but are not limited to,specifically binding to human and/or cynomologus HER3; the antibodybinds to HER3 and inhibits HER3 biological activity by inhibiting theHER signaling activity in a phospho-HER assay.

The functional properties of the altered antibodies can be assessedusing standard assays available in the art and/or described herein, suchas those set forth in the Examples (e.g., ELISAs).

In certain embodiments of the methods of engineering antibodies of theinvention, mutations can be introduced randomly or selectively along allor part of an antibody or fragment coding sequence and the resultingmodified HER3 antibodies can be screened for binding activity and/orother functional properties as described herein. Mutational methods havebeen described in the art. For example, PCT Publication WO 02/092780 byShort describes methods for creating and screening antibody mutationsusing saturation mutagenesis, synthetic ligation assembly, or acombination thereof. Alternatively, PCT Publication WO 03/074679 byLazar et al. describes methods of using computational screening methodsto optimize physiochemical properties of antibodies.

Characterization of the Antibodies of the Invention

The antibodies of the invention can be characterized by variousfunctional assays. For example, they can be characterized by theirability to inhibit biological activity by inhibiting HER signaling in aphospho-HER assay as described herein, their affinity to a HER3 protein(e.g., human and/or cynomologus HER3), the epitope binning, theirresistance to proteolysis, and their ability to block HER3 downstreamsignaling. Various methods can be used to measure HER3-mediatedsignaling. For example, the HER signaling pathway can be monitored by(i) measurement of phospho-HER3; (ii) measurement of phosphorylation ofHER3 or other downstream signaling proteins (e.g. Akt), (iii) ligandblocking assays as described herein, (iv) heterodimer formation, (v)HER3 dependent gene expression signature, (vi) receptor internalization,and (vii) HER3 driven cell phenotypes (e.g. proliferation).

The ability of an antibody to bind to HER3 can be detected by labellingthe antibody of interest directly, or the antibody may be unlabelled andbinding detected indirectly using various sandwich assay formats knownin the art.

In some embodiments, the HER3 antibodies block or compete with bindingof a reference HER3 antibody to a HER3. These can be fully human HER3antibodies described above. They can also be other mouse, chimeric orhumanized HER3 antibodies which bind to the same epitope as thereference antibody. The capacity to block or compete with the referenceantibody binding indicates that a HER3 antibody under test binds to thesame or similar epitope as that defined by the reference antibody, or toan epitope which is sufficiently proximal to the epitope bound by thereference HER3 antibody. Such antibodies are especially likely to sharethe advantageous properties identified for the reference antibody. Thecapacity to block or compete with the reference antibody may bedetermined by, e.g., a competition binding assay. With a competitionbinding assay, the antibody under test is examined for ability toinhibit specific binding of the reference antibody to a common antigen,such as a HER3 polypeptide or protein. A test antibody competes with thereference antibody for specific binding to the antigen if an excess ofthe test antibody substantially inhibits binding of the referenceantibody. Substantial inhibition means that the test antibody reducesspecific binding of the reference antibody usually by at least 10%, 25%,50%, 75%, or 90%.

There are a number of known competition binding assays that can be usedto assess competition of a HER3 antibody with the reference HER3antibody for binding to a HER3. These include, e.g., solid phase director indirect radioimmunoassay (RIA), solid phase direct or indirectenzyme immunoassay (EIA), sandwich competition assay (see Stahli et al.,(1983) Methods in Enzymology 9:242-253); solid phase directbiotin-avidin EIA (see Kirkland et al., (1986) J. Immunol.137:3614-3619); solid phase direct labeled assay, solid phase directlabeled sandwich assay (see Harlow & Lane, supra); solid phase directlabel RIA using 1-125 label (see Morel et al., (1988) Molec. Immunol.25:7-15); solid phase direct biotin-avidin EIA (Cheung et al., (1990)Virology 176:546-552); and direct labeled RIA (Moldenhauer et al.,(1990) Scand. J. Immunol. 32:77-82). Typically, such an assay involvesthe use of purified antigen bound to a solid surface or cells bearingeither of these, an unlabelled test HER3-binding antibody and a labelledreference antibody. Competitive inhibition is measured by determiningthe amount of label bound to the solid surface or cells in the presenceof the test antibody. Usually the test antibody is present in excess.Antibodies identified by competition assay (competing antibodies)include antibodies binding to the same epitope as the reference antibodyand antibodies binding to an adjacent epitope sufficiently proximal tothe epitope bound by the reference antibody for steric hindrance tooccur.

To determine if the selected HER3 monoclonal antibodies bind to uniqueepitopes, each antibody can be biotinylated using commercially availablereagents (e.g., reagents from Pierce, Rockford, Ill.). Competitionstudies using unlabeled monoclonal antibodies and biotinylatedmonoclonal antibodies can be performed using a HER3 polypeptidecoated-ELISA plates. Biotinylated MAb binding can be detected with astrep-avidin-alkaline phosphatase probe. To determine the isotype of apurified HER3-binding antibody, isotype ELISAs can be performed. Forexample, wells of microtiter plates can be coated with 1 μg/ml ofanti-human IgG overnight at 4° C. After blocking with 1% BSA, the platesare reacted with 1 μg/ml or less of the monoclonal HER3 antibody orpurified isotype controls, at ambient temperature for one to two hours.The wells can then be reacted with either human IgG1 or humanIgM-specific alkaline phosphatase-conjugated probes. Plates are thendeveloped and analyzed so that the isotype of the purified antibody canbe determined.

To demonstrate binding of monoclonal HER3 antibodies to live cellsexpressing a HER3 polypeptide, flow cytometry can be used. Briefly, celllines expressing HER3 (grown under standard growth conditions) can bemixed with various concentrations of a HER3-binding antibody in PBScontaining 0.1% BSA and 10% fetal calf serum, and incubated at 4° C. for1 hour. After washing, the cells are reacted with Fluorescein-labeledanti-human IgG antibody under the same conditions as the primaryantibody staining. The samples can be analyzed by FACScan instrumentusing light and side scatter properties to gate on single cells. Analternative assay using fluorescence microscopy may be used (in additionto or instead of) the flow cytometry assay. Cells can be stained exactlyas described above and examined by fluorescence microscopy. This methodallows visualization of individual cells, but may have diminishedsensitivity depending on the density of the antigen.

The antibodies or fragments thereof of the invention can be furthertested for reactivity with a HER3 polypeptide or antigenic fragment byWestern blotting. Briefly, purified HER3 polypeptides or fusionproteins, or cell extracts from cells expressing HER3 can be preparedand subjected to sodium dodecyl sulfate polyacrylamide gelelectrophoresis. After electrophoresis, the separated antigens aretransferred to nitrocellulose membranes, blocked with 10% fetal calfserum, and probed with the monoclonal antibodies to be tested. Human IgGbinding can be detected using anti-human IgG alkaline phosphatase anddeveloped with BCIP/NBT substrate tablets (Sigma Chem. Co., St. Louis,Mo.).

A number of readouts can be used to assess the efficacy, andspecificity, of HER3 antibodies in cell-based assays of ligand-inducedheterodimer formation. Activity can be assessed by one or more of thefollowing:

(i) Inhibition of ligand-induced heterodimerisation of HER2 with otherEGF family members in a target cell line, for example MCF-7 breastcancer cells. Immunoprecipitation of HER2 complexes from cell lysatescan be performed with a receptor-specific antibody, and theabsence/presence of other EGF receptors and their biologically relevantligands within the complex can be analysed followingelectrophoresis/Western transfer by probing with antibodies to other EGFreceptors.

(ii) Inhibition of the activation of signaling pathways byligand-activated heterodimers.

Association with HER3 appears key for other members of the EGF family ofreceptors to elicit maximal cellular response following ligand binding.In the case of the kinase-defective HER3, HER2 provides a functionaltyrosine kinase domain to enable signaling to occur following binding ofgrowth factor ligands. Thus, cells co-expressing HER2 and HER3 can betreated with ligand, for example heregulin, in the absence and presenceof inhibitor and the effect on HER3 tyrosine phosphorylation monitoredby a number of ways including immunoprecipitation of HER3 from treatedcell lysates and subsequent Western blotting using anti-phosphotyrosineantibodies (see Agus op. cit. for details). Alternatively, ahigh-throughput assay can be developed by trapping HER3 from solubilizedlysates onto the wells of a 96-well plate coated with an anti-HER3receptor antibody, and the level of tyrosine phosphorylation measuredusing, for example, europium-labelled anti-phosphotyrosine antibodies,as embodied by Waddleton et al., (2002) Anal. Biochem. 309:150-157.

In a broader extension of this approach, effector molecules known to beactivated downstream of activated receptor heterodimers, such asmitogen-activated protein kinases (MAPK) and Akt, may be analyseddirectly, by immunoprecipitation from treated lysates and blotting withantibodies that detect the activated forms of these proteins, or byanalysing the ability of these proteins to modify/activate specificsubstrates.

(iii) Inhibition of ligand-induced cellular proliferation. A variety ofcell lines are known to co-express combinations of ErbB receptors, forexample many breast and prostate cancer cell lines. Assays may beperformed in 24/48/96-well formats with the readout based around DNAsynthesis (tritiated thymidine incorporation), increase in cell number(crystal violet staining) etc.

A number of readouts can be used to assess the efficacy, andspecificity, of HER3 antibodies in cell-based assays ofligand-independent homo- and heterodimer formation. For example, HER2overexpression triggers ligand-independent activation of the kinasedomain as a result of spontaneous dimer formation. Over expressed HER2generates either homo- or heterodimers with other HER molecules such asHER1, HER3 and HER4.

Ability of antibodies or fragments thereof to block in vivo growth oftumour xenografts of human tumour cell lines whose tumorigenic phenotypeis known to be at least partly dependent on ligand activation of HER3heterodimer cell signaling e.g. BxPC3 pancreatic cancer cells etc. Thiscan be assessed in immunocompromised mice either alone or in combinationwith an appropriate cytotoxic agent for the cell line in question.Examples of functional assays are also described in the Example sectionbelow.

Prophylactic and Therapeutic Uses

The present invention provides methods of treating a disease or disorderassociated with the HER3 signaling pathway by administering to a subjectin need thereof an effective amount of the antibody or fragment thereofof the invention. In a specific embodiment, the present inventionprovides a method of treating or preventing cancers (e.g., breastcancer, colorectal cancer, lung cancer, multiple myeloma, ovariancancer, liver cancer, gastric cancer, pancreatic cancer, acute myeloidleukemia, chronic myeloid leukemia, osteosarcoma, squamous cellcarcinoma, peripheral nerve sheath tumors, schwannoma, head and neckcancer, bladder cancer, esophageal cancer, Barretts esophageal cancer,glioblastoma, clear cell sarcoma of soft tissue, malignant mesothelioma,neurofibromatosis, renal cancer, melanoma, prostate cancer, benignprostatic hyperplasia (BPH), gynacomastica, and endometriosis) byadministering to a subject in need thereof an effective amount of theantibodies or fragments thereof of the invention. In some embodiments,the present invention provides methods of treating or preventing cancersassociated with a HER3 signaling pathway by administering to a subjectin need thereof an effective amount of the antibodies of the invention.

In a specific embodiment, the present invention provides methods oftreating cancers associated with a HER3 signaling pathway that include,but are not limited to breast cancer, colorectal cancer, lung cancer,multiple myeloma, ovarian cancer, liver cancer, gastric cancer,pancreatic cancer, acute myeloid leukemia, chronic myeloid leukemia,osteosarcoma, squamous cell carcinoma, peripheral nerve sheath tumorsschwannoma, head and neck cancer, bladder cancer, esophageal cancer,Barretts esophageal cancer, glioblastoma, clear cell sarcoma of softtissue, malignant mesothelioma, neurofibromatosis, renal cancer,melanoma, prostate cancer, benign prostatic hyperplasia (BPH),gynacomastica, and endometriosis.

The antibodies or fragments thereof of the invention can also be used totreat or prevent other disorders associated with aberrant or defectiveHER3 signaling, including but are not limited to respiratory diseases,osteoporosis, osteoarthritis, polycystic kidney disease, diabetes,schizophrenia, vascular disease, cardiac disease, non-oncogenicproliferative diseases, fibrosis, and neurodegenerative diseases such asAlzheimer's disease.

Suitable agents for combination treatment with HER3 antibodies includestandard of care agents known in the art that are able to modulate theErbB signaling pathway. Suitable examples of standard of care agents forHER2 include, but are not limited to Herceptin and Tykerb. Suitableexamples of standard of care agents for EGFR include, but are notlimited to Iressa, Tarceva, Erbitux and Vectibix as described above.Other agents that may be suitable for combination treatment with HER3antibodies include, but are not limited to those that modulate receptortyrosine kinases, G-protein coupled receptors, growth/survival signaltransduction pathways, nuclear hormone receptors, apoptotic pathways,cell cycle and angiogenesis.

Diagnostic Uses

In one aspect, the invention encompasses diagnostic assays fordetermining HER3 and/or nucleic acid expression as well as HER3 proteinfunction, in the context of a biological sample (e.g., blood, serum,cells, tissue) or from individual afflicted with cancer, or is at riskof developing cancer.

Diagnostic assays, such as competitive assays rely on the ability of alabelled analogue (the “tracer”) to compete with the test sample analytefor a limited number of binding sites on a common binding partner. Thebinding partner generally is insolubilized before or after thecompetition and then the tracer and analyte bound to the binding partnerare separated from the unbound tracer and analyte. This separation isaccomplished by decanting (where the binding partner waspreinsolubilized) or by centrifuging (where the binding partner wasprecipitated after the competitive reaction). The amount of test sampleanalyte is inversely proportional to the amount of bound tracer asmeasured by the amount of marker substance. Dose-response curves withknown amounts of analyte are prepared and compared with the test resultsin order to quantitatively determine the amount of analyte present inthe test sample. These assays are called ELISA systems when enzymes areused as the detectable markers. In an assay of this form, competitivebinding between antibodies and HER3 antibodies results in the boundHER3, preferably the HER3 epitopes of the invention, being a measure ofantibodies in the serum sample, most particularly, inhibiting antibodiesin the serum sample.

A significant advantage of the assay is that measurement is made ofinhibiting antibodies directly (i.e., those which interfere with bindingof HER3, specifically, epitopes). Such an assay, particularly in theform of an ELISA test has considerable applications in the clinicalenvironment and in routine blood screening.

Another aspect of the invention provides methods for determining HER3nucleic acid expression or HER3 activity in an individual to therebyselect appropriate therapeutic or prophylactic agents for thatindividual (referred to herein as “pharmacogenomics”). Pharmacogenomicsallows for the selection of agents (e.g., drugs) for therapeutic orprophylactic treatment of an individual based on the genotype of theindividual (e.g., the genotype of the individual examined to determinethe ability of the individual to respond to a particular agent.)

Yet another aspect of the invention pertains to monitoring the influenceof agents (e.g., drugs) on the expression or activity of HER3 inclinical trials.

Pharmaceutical Compositions

To prepare pharmaceutical or sterile compositions including antibodiesor fragments thereof, the antibodies or fragments thereof are mixed witha pharmaceutically acceptable carrier or excipient. The compositions canadditionally contain one or more other therapeutic agents that aresuitable for treating or preventing cancer (breast cancer, colorectalcancer, lung cancer, multiple myeloma, ovarian cancer, liver cancer,gastric cancer, pancreatic cancer, acute myeloid leukemia, chronicmyeloid leukemia, osteosarcoma, squamous cell carcinoma, peripheralnerve sheath tumors schwannoma, head and neck cancer, bladder cancer,esophageal cancer, glioblastoma, clear cell sarcoma of soft tissue,malignant mesothelioma, neurofibromatosis, renal cancer, and melanoma,Barretts esophageal cancer, prostate cancer, benign prostatichyperplasia (BPH), gynacomastica, and endometriosis).

Formulations of therapeutic and diagnostic agents can be prepared bymixing with physiologically acceptable carriers, excipients, orstabilizers in the form of, e.g., lyophilized powders, slurries, aqueoussolutions, lotions, or suspensions (see, e.g., Hardman et al., (2001)Goodman and Gilman's The Pharmacological Basis of Therapeutics,McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science andPractice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.;Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: ParenteralMedications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990)Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, etal. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, MarcelDekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety,Marcel Dekker, Inc., New York, N.Y.).

Selecting an administration regimen for a therapeutic depends on severalfactors, including the serum or tissue turnover rate of the entity, thelevel of symptoms, the immunogenicity of the entity, and theaccessibility of the target cells in the biological matrix. In certainembodiments, an administration regimen maximizes the amount oftherapeutic delivered to the patient consistent with an acceptable levelof side effects. Accordingly, the amount of biologic delivered dependsin part on the particular entity and the severity of the condition beingtreated. Guidance in selecting appropriate doses of antibodies,cytokines, and small molecules are available (see, e.g., Wawrzynczak(1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK;Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis,Marcel Dekker, New York, N.Y.; Bach (ed.) (1993) Monoclonal Antibodiesand Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York,N.Y.; Baert et al., (2003) New Engl. J. Med. 348:601-608; Milgrom etal., (1999) New Engl. J. Med. 341:1966-1973; Slamon et al., (2001) NewEngl. J. Med. 344:783-792; Beniaminovitz et al., (2000) New Engl. J.Med. 342:613-619; Ghosh et al., (2003) New Engl. J. Med. 348:24-32;Lipsky et al., (2000) New Engl. J. Med. 343:1594-1602).

Determination of the appropriate dose is made by the clinician, e.g.,using parameters or factors known or suspected in the art to affecttreatment or predicted to affect treatment. Generally, the dose beginswith an amount somewhat less than the optimum dose and it is increasedby small increments thereafter until the desired or optimum effect isachieved relative to any negative side effects. Important diagnosticmeasures include those of symptoms of, e.g., the inflammation or levelof inflammatory cytokines produced.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of the present invention may be varied so as to obtain anamount of the active ingredient which is effective to achieve thedesired therapeutic response for a particular patient, composition, andmode of administration, without being toxic to the patient. The selecteddosage level will depend upon a variety of pharmacokinetic factorsincluding the activity of the particular compositions of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compositions employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors known in the medical arts.

Compositions comprising antibodies or fragments thereof of the inventioncan be provided by continuous infusion, or by doses at intervals of,e.g., one day, one week, or 1-7 times per week. Doses may be providedintravenously, subcutaneously, topically, orally, nasally, rectally,intramuscular, intracerebrally, or by inhalation. A specific doseprotocol is one involving the maximal dose or dose frequency that avoidssignificant undesirable side effects.

A total weekly dose may be at least 0.05 μg/kg body weight, at least 0.2μg/kg, at least 0.5 μg/kg, at least 1 μg/kg, at least 10 μg/kg, at least100 μg/kg, at least 0.2 mg/kg, at least 1.0 mg/kg, at least 2.0 mg/kg,at least 10 mg/kg, at least 25 mg/kg, or at least 50 mg/kg (see, e.g.,Yang et al., (2003) New Engl. J. Med. 349:427-434; Herold et al., (2002)New Engl. J. Med. 346:1692-1698; Liu et al., (1999) J. Neurol.Neurosurg. Psych. 67:451-456; Portielji et al., (2003) Cancer Immunol.Immunother. 52:133-144). The desired dose of antibodies or fragmentsthereof is about the same as for an antibody or polypeptide, on amoles/kg body weight basis. The desired plasma concentration of theantibodies or fragments thereof is about, on a moles/kg body weightbasis. The dose may be at least 15 μg at least 20 μg, at least 25 μg, atleast 30 μg, at least 35 μg, at least 40 μg, at least 45 μg, at least 50μg, at least 55 μg, at least 60 μg, at least 65 μg, at least 70 μg, atleast 75 μg, at least 80 μg, at least 85 μg, at least 90 μg, at least 95μg, or at least 100 μg. The doses administered to a subject may numberat least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or more.

For antibodies or fragments thereof the invention, the dosageadministered to a patient may be 0.0001 mg/kg to 100 mg/kg of thepatient's body weight. The dosage may be between 0.0001 mg/kg and 20mg/kg, 0.0001 mg/kg and 10 mg/kg, 0.0001 mg/kg and 5 mg/kg, 0.0001 and 2mg/kg, 0.0001 and 1 mg/kg, 0.0001 mg/kg and 0.75 mg/kg, 0.0001 mg/kg and0.5 mg/kg, 0.0001 mg/kg to 0.25 mg/kg, 0.0001 to 0.15 mg/kg, 0.0001 to0.10 mg/kg, 0.001 to 0.5 mg/kg, 0.01 to 0.25 mg/kg or 0.01 to 0.10 mg/kgof the patient's body weight.

The dosage of the antibodies or fragments thereof of the invention maybe calculated using the patient's weight in kilograms (kg) multiplied bythe dose to be administered in mg/kg. The dosage of the antibodies orfragments thereof the invention may be 150 μg/kg or less, 125 μg/kg orless, 100 μg/kg or less, 95 μg/kg or less, 90 μg/kg or less, 85 μg/kg orless, 80 μg/kg or less, 75 μg/kg or less, 70 μg/kg or less, 65 μg/kg orless, 60 μg/kg or less, 55 μg/kg or less, 50 μg/kg or less, 45 μg/kg orless, 40 μg/kg or less, 35 μg/kg or less, 30 μg/kg or less, 25 μg/kg orless, 20 μg/kg or less, 15 μg/kg or less, 10 μg/kg or less, 5 μg/kg orless, 2.5 μg/kg or less, 2 μg/kg or less, 1.5 μg/kg or less, 1 μg/kg orless, 0.5 μg/kg or less, or 0.5 μg/kg or less of a patient's bodyweight.

Unit dose of the antibodies or fragments thereof the invention may be0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mgto 7 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5mg, or 1 mg to 2.5 mg.

The dosage of the antibodies or fragments thereof the invention mayachieve a serum titer of at least 0.1 μg/ml, at least 0.5 μg/ml, atleast 1 μg/ml, at least 2 μg/ml, at least 5 μg/ml, at least 6 μg/ml, atleast 10 μg/ml, at least 15 μg/ml, at least 20 μg/ml, at least 25 μg/ml,at least 50 μg/ml, at least 100 μg/ml, at least 125 μg/ml, at least 150μg/ml, at least 175 μg/ml, at least 200 μg/ml, at least 225 μg/ml, atleast 250 μg/ml, at least 275 μg/ml, at least 300 μg/ml, at least 325μg/ml, at least 350 μg/ml, at least 375 μg/ml, or at least 400 μg/ml ina subject.

Alternatively, the dosage of the antibodies or fragments thereof theinvention may achieve a serum titer of at least 0.1 μg/ml, at least 0.5μg/ml, at least 1 μg/ml, at least, 2 μg/ml, at least 5 μg/ml, at least 6μg/ml, at least 10 μg/ml, at least 15 μg/ml, at least 20 .mu.g/ml, atleast 25 μg/ml, at least 50 μg/ml, at least 100 μg/ml, at least 125μg/ml, at least 150 μg/mμ, at least 175 μg/ml, at least 200 μg/ml, atleast 225 μg/ml, at least 250 μg/ml, at least 275 μg/ml, at least 300μg/ml, at least 325 μg/ml, at least 350 μg/ml, at least 375 μg/ml, or atleast 400 μg/ml in the subject.

Doses of antibodies or fragments thereof the invention may be repeatedand the administrations may be separated by at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, or at least 6 months.

An effective amount for a particular patient may vary depending onfactors such as the condition being treated, the overall health of thepatient, the method route and dose of administration and the severity ofside affects (see, e.g., Maynard et al., (1996) A Handbook of SOPs forGood Clinical Practice, Interpharm Press, Boca Raton, Fla.; Dent (2001)Good Laboratory and Good Clinical Practice, Urch Publ., London, UK).

The route of administration may be by, e.g., topical or cutaneousapplication, injection or infusion by intravenous, intraperitoneal,intracerebral, intramuscular, intraocular, intraarterial,intracerebrospinal, intralesional, or by sustained release systems or animplant (see, e.g., Sidman et al., (1983) Biopolymers 22:547-556; Langeret al., (1981) J. Biomed. Mater. Res. 15:167-277; Langer (1982) Chem.Tech. 12:98-105; Epstein et al., (1985) Proc. Natl. Acad. Sci. USA82:3688-3692; Hwang et al., (1980) Proc. Natl. Acad. Sci. USA77:4030-4034; U.S. Pat. Nos. 6,350,466 and 6,316,024). Where necessary,the composition may also include a solubilizing agent and a localanesthetic such as lidocaine to ease pain at the site of the injection.In addition, pulmonary administration can also be employed, e.g., by useof an inhaler or nebulizer, and formulation with an aerosolizing agent.See, e.g., U.S. Pat. Nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272,5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos.WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903,each of which is incorporated herein by reference their entirety.

A composition of the present invention may also be administered via oneor more routes of administration using one or more of a variety ofmethods known in the art. As will be appreciated by the skilled artisan,the route and/or mode of administration will vary depending upon thedesired results. Selected routes of administration for antibodies orfragments thereof the invention include intravenous, intramuscular,intradermal, intraperitoneal, subcutaneous, spinal or other parenteralroutes of administration, for example by injection or infusion.Parenteral administration may represent modes of administration otherthan enteral and topical administration, usually by injection, andincludes, without limitation, intravenous, intramuscular, intraarterial,intrathecal, intracapsular, intraorbital, intracardiac, intradermal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, epidural andintrasternal injection and infusion. Alternatively, a composition of theinvention can be administered via a non-parenteral route, such as atopical, epidermal or mucosal route of administration, for example,intranasally, orally, vaginally, rectally, sublingually or topically. Inone embodiment, the antibodies or fragments thereof of the invention isadministered by infusion. In another embodiment, the multispecificepitope binding protein of the invention is administered subcutaneously.

If the antibodies or fragments thereof of the invention are administeredin a controlled release or sustained release system, a pump may be usedto achieve controlled or sustained release (see Langer, supra; Sefton,(1987) CRC Crit. Ref Biomed. Eng. 14:20; Buchwald et al., (1980),Surgery 88:507; Saudek et al., (1989) N. Engl. J. Med. 321:574).Polymeric materials can be used to achieve controlled or sustainedrelease of the therapies of the invention (see e.g., MedicalApplications of Controlled Release, Langer and Wise (eds.), CRC Pres.,Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Ranger and Peppas, (1983) J. Macromol. Sci. Rev. Macromol. Chem. 23:61;see also Levy et al., (1985) Science 228:190; During et al., (1989) Ann.Neurol. 25:351; Howard et al., (1989) J. Neurosurg. 7 1:105); U.S. Pat.No. 5,679,377; U.S. Pat. No. 5,916,597; U.S. Pat. No. 5,912,015; U.S.Pat. No. 5,989,463; U.S. Pat. No. 5,128,326; PCT Publication No. WO99/15154; and PCT Publication No. WO 99/20253. Examples of polymers usedin sustained release formulations include, but are not limited to,poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate),poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylicacid), polyglycolides (PLG), polyanhydrides, poly(N-vinyl pyrrolidone),poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactides(PLA), poly(lactide-co-glycolides) (PLGA), and polyorthoesters. In oneembodiment, the polymer used in a sustained release formulation isinert, free of leachable impurities, stable on storage, sterile, andbiodegradable. A controlled or sustained release system can be placed inproximity of the prophylactic or therapeutic target, thus requiring onlya fraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).

Controlled release systems are discussed in the review by Langer,(1990), Science 249:1527-1533). Any technique known to one of skill inthe art can be used to produce sustained release formulations comprisingone or more antibodies or fragments thereof the invention. See, e.g.,U.S. Pat. No. 4,526,938, PCT publication WO 91/05548, PCT publication WO96/20698, Ning et al., (1996), Radiotherapy & Oncology 39:179-189, Songet al., (1995) PDA Journal of Pharmaceutical Science & Technology50:372-397, Cleek et al., (1997) Pro. Int'l. Symp. Control. Rel. Bioact.Mater. 24:853-854, and Lam et al., (1997) Proc. Int'l. Symp. ControlRel. Bioact. Mater. 24:759-760, each of which is incorporated herein byreference in their entirety.

If the antibodies or fragments thereof of the invention are administeredtopically, they can be formulated in the form of an ointment, cream,transdermal patch, lotion, gel, shampoo, spray, aerosol, solution,emulsion, or other form well-known to one of skill in the art. See,e.g., Remington's Pharmaceutical Sciences and Introduction toPharmaceutical Dosage Forms, 19th ed., Mack Pub. Co., Easton, Pa.(1995). For non-sprayable topical dosage forms, viscous to semi-solid orsolid forms comprising a carrier or one or more excipients compatiblewith topical application and having a dynamic viscosity, in someinstances, greater than water are typically employed. Suitableformulations include, without limitation, solutions, suspensions,emulsions, creams, ointments, powders, liniments, salves, and the like,which are, if desired, sterilized or mixed with auxiliary agents (e.g.,preservatives, stabilizers, wetting agents, buffers, or salts) forinfluencing various properties, such as, for example, osmotic pressure.Other suitable topical dosage forms include sprayable aerosolpreparations wherein the active ingredient, in some instances, incombination with a solid or liquid inert carrier, is packaged in amixture with a pressurized volatile (e.g., a gaseous propellant, such asfreon) or in a squeeze bottle. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms if desired.Examples of such additional ingredients are well-known in the art.

If the compositions comprising antibodies or fragments thereof areadministered intranasally, it can be formulated in an aerosol form,spray, mist or in the form of drops. In particular, prophylactic ortherapeutic agents for use according to the present invention can beconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebuliser, with the use of a suitable propellant(e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridges(composed of, e.g., gelatin) for use in an inhaler or insufflator may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

Methods for co-administration or treatment with a second therapeuticagent, e.g., a cytokine, steroid, chemotherapeutic agent, antibiotic, orradiation, are known in the art (see, e.g., Hardman et al., (eds.)(2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics,10.sup.th ed., McGraw-Hill, New York, N.Y.; Poole and Peterson (eds.)(2001) Pharmacotherapeutics for Advanced Practice: A Practical Approach,Lippincott, Williams & Wilkins, Phila., Pa.; Chabner and Longo (eds.)(2001) Cancer Chemotherapy and Biotherapy, Lippincott, Williams &Wilkins, Phila., Pa.). An effective amount of therapeutic may decreasethe symptoms by at least 10%; by at least 20%; at least about 30%; atleast 40%, or at least 50%.

Additional therapies (e.g., prophylactic or therapeutic agents), whichcan be administered in combination with the antibodies or fragmentsthereof the invention may be administered less than 5 minutes apart,less than 30 minutes apart, 1 hour apart, at about 1 hour apart, atabout 1 to about 2 hours apart, at about 2 hours to about 3 hours apart,at about 3 hours to about 4 hours apart, at about 4 hours to about 5hours apart, at about 5 hours to about 6 hours apart, at about 6 hoursto about 7 hours apart, at about 7 hours to about 8 hours apart, atabout 8 hours to about 9 hours apart, at about 9 hours to about 10 hoursapart, at about 10 hours to about 11 hours apart, at about 11 hours toabout 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart,48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or96 hours to 120 hours apart from the antibodies or fragments thereof theinvention. The two or more therapies may be administered within one samepatient visit.

The antibodies or fragments thereof the invention and the othertherapies may be cyclically administered. Cycling therapy involves theadministration of a first therapy (e.g., a first prophylactic ortherapeutic agent) for a period of time, followed by the administrationof a second therapy (e.g., a second prophylactic or therapeutic agent)for a period of time, optionally, followed by the administration of athird therapy (e.g., prophylactic or therapeutic agent) for a period oftime and so forth, and repeating this sequential administration, i.e.,the cycle in order to reduce the development of resistance to one of thetherapies, to avoid or reduce the side effects of one of the therapies,and/or to improve the efficacy of the therapies.

In certain embodiments, the antibodies or fragments thereof theinvention can be formulated to ensure proper distribution in vivo. Forexample, the blood-brain barrier (BBB) excludes many highly hydrophiliccompounds. To ensure that the therapeutic compounds of the inventioncross the BBB (if desired), they can be formulated, for example, inliposomes. For methods of manufacturing liposomes, see, e.g., U.S. Pat.Nos. 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise oneor more moieties which are selectively transported into specific cellsor organs, thus enhance targeted drug delivery (see, e.g., Ranade,(1989) J. Clin. Pharmacol. 29:685). Exemplary targeting moieties includefolate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al);mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun.153:1038); antibodies (Bloeman et al., (1995) FEBS Lett. 357:140; Owaiset al., (1995) Antimicrob. Agents Chemother. 39:180); surfactant proteinA receptor (Briscoe et al., (1995) Am. J. Physiol. 1233:134); p 120(Schreier et al, (1994) J. Biol. Chem. 269:9090); see also K. Keinanen;M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler(1994) Immunomethods 4:273.

The invention provides protocols for the administration ofpharmaceutical composition comprising antibodies or fragments thereofthe invention alone or in combination with other therapies to a subjectin need thereof. The therapies (e.g., prophylactic or therapeuticagents) of the combination therapies of the present invention can beadministered concomitantly or sequentially to a subject. The therapy(e.g., prophylactic or therapeutic agents) of the combination therapiesof the present invention can also be cyclically administered. Cyclingtherapy involves the administration of a first therapy (e.g., a firstprophylactic or therapeutic agent) for a period of time, followed by theadministration of a second therapy (e.g., a second prophylactic ortherapeutic agent) for a period of time and repeating this sequentialadministration, i.e., the cycle, in order to reduce the development ofresistance to one of the therapies (e.g., agents) to avoid or reduce theside effects of one of the therapies (e.g., agents), and/or to improve,the efficacy of the therapies.

The therapies (e.g., prophylactic or therapeutic agents) of thecombination therapies of the invention can be administered to a subjectconcurrently. The term “concurrently” is not limited to theadministration of therapies (e.g., prophylactic or therapeutic agents)at exactly the same time, but rather it is meant that a pharmaceuticalcomposition comprising antibodies or fragments thereof the invention areadministered to a subject in a sequence and within a time interval suchthat the antibodies of the invention can act together with the othertherapy(ies) to provide an increased benefit than if they wereadministered otherwise. For example, each therapy may be administered toa subject at the same time or sequentially in any order at differentpoints in time; however, if not administered at the same time, theyshould be administered sufficiently close in time so as to provide thedesired therapeutic or prophylactic effect. Each therapy can beadministered to a subject separately, in any appropriate form and by anysuitable route. In various embodiments, the therapies (e.g.,prophylactic or therapeutic agents) are administered to a subject lessthan 15 minutes, less than 30 minutes, less than 1 hour apart, at about1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hoursto about 3 hours apart, at about 3 hours to about 4 hours apart, atabout 4 hours to about 5 hours apart, at about 5 hours to about 6 hoursapart, at about 6 hours to about 7 hours apart, at about 7 hours toabout 8 hours apart, at about 8 hours to about 9 hours apart, at about 9hours to about 10 hours apart, at about 10 hours to about 11 hoursapart, at about 11 hours to about 12 hours apart, 24 hours apart, 48hours apart, 72 hours apart, or 1 week apart. In other embodiments, twoor more therapies (e.g., prophylactic or therapeutic agents) areadministered to a within the same patient visit.

The prophylactic or therapeutic agents of the combination therapies canbe administered to a subject in the same pharmaceutical composition.Alternatively, the prophylactic or therapeutic agents of the combinationtherapies can be administered concurrently to a subject in separatepharmaceutical compositions. The prophylactic or therapeutic agents maybe administered to a subject by the same or different routes ofadministration.

The invention having been fully described, it is further illustrated bythe following examples and claims, which are illustrative and are notmeant to be further limiting.

EXAMPLES Example 1 Methods, Materials and Screening for Antibodies (i)Cell Lines

SK-Br-3, BT-474 and MCF-7 cell lines were purchased from ATCC androutinely maintained in growth media supplemented with 10% fetal bovineserum (FBS).

(Ii) Generation of Recombinant Human, Cyno, Mouse and Rat HER3 Vectors

Murine HER3 extracellular domain was PCR amplified from mouse brain cDNA(Clontech) and sequence verified by comparison with Refseq NM_(—)010153.Rat HER3 ECD was reverse transcribed from Rat-2 cell mRNA and sequenceverified by comparison with NM_(—)017218. Cynomolgus HER3 cDNA templatewas generated using RNA from various cyno tissues (Zyagen Laboratories),and the RT-PCR product cloned into pCR®-TOPO-XL (Invitrogen) prior tosequencing of both strands. Human HER3 was derived from a human fetalbrain cDNA library (Source) and sequence verified by comparison withNM_(—)001982.

To generate tagged recombinant proteins, human, mouse, rat and cyno HER3was PCR amplified using Pwo Taq polymerase (Roche Diagnostics).Amplified PCR products were gel purified and cloned into a pDonR201(Invitrogen) gateway entry vector that had previously been modified toinclude an in-frame N-terminal CD33 leader sequence and a C-terminalTAG, e.g., FLAG TAG. The TAG allows purification of monomeric proteinsvia an anti-TAG monoclonal antibody. The target genes were flanked withAttB1 and AttB2 allowing recombination into Gateway adapted proprietarydestination vectors (e.g., pcDNA3.1) using the Gateway® cloningtechnology (Invitrogen). Recombination reactions were performed using aGateway LR reaction with proprietary destination vectors containing aCMV promoter to create the TAG expression vectors, although anycommercially available vector can be used.

Further recombinant HER3 proteins were generated that fused the HER3 ECDupstream of a C-terminal Factor X cleavage site and the human IgG hingeand Fc domain to create an Fc-tagged protein. To achieve this, thevarious HER3 ECD's were PCR amplified and cloned into a vector (e.g.,pcDNA3.1) modified to contain an in-frame C-terminal fusion of Factor Xsite-Hinge-hFc. The generated open reading frame was flanked with AttBand AttB2 sites for further cloning with the Gateway® recombinantcloning technology (Invitrogen). An LR Gateway reaction was used totransfer HER3-Fc into a destination expression construct containing aCMV promoter. HER3 point mutation expression constructs were generatedusing standard site directed mutagenesis protocols and the resultantvectors sequence verified.

TABLE 3 Generation of HER3 expression vectors. HER3 amino acid numberingis based on NP_001973 (human), NP_034283 (mouse) and NP_058914 (rat).Name Description Hu HER3 CD33-[Human HER3, residues 20-640]-TAG Mu HER3CD33-[Murine HER3, residues 20-643]-TAG Rat HER3 CD33-[Rat HER3,residues 20-643]-TAG Cyno HER3 CD33-[Cyno HER3, residues 20-643]-TAGHER3 D1-2 CD33-[Human HER3, residues 20-329]-TAG HER3 D2 CD33-[HumanHER3, residues 185-329]-TAG HER3 D3-4 CD33-[Human HER3, residues330-643]-TAG HER3 D3 CD33-[Human HER3, residues 330-495]-TAG HER3 D4CD33-[Human HER3, residues 496-643]-TAG Hu HER3-Fc [Human HER3, residues1-643]-Fc Mu HER3-Fc [Murine HER3, residues 1-643]-Fc Cyno HER3-Fc [CynoHER3, residues 1-643]-Fc Rat HER3-Fc [Rat HER3, residues 1-643]-Fc HER3D2-Fc [Human HER3 residues 207-329]-Fc(iii) Expression of Recombinant HER3 Proteins

The desired HER3 recombinant proteins were expressed in HEK293 derivedcell lines previously adapted to suspension culture and grown in aNovartis proprietary serum-free medium. Small scale expressionverification was undertaken in transient 6-well-plate transfectionassays on the basis of lipofection. Large-scale protein production viatransient transfection and was performed at the 10-20 L scale in theWave™ bioreactor system (Wave Biotech). DNA Polyethylenimine(Polysciences) was used as a plasmid carrier at a ratio of 1:3 (w:w).The cell culture supernatants were harvested 7-10 days post transfectionand concentrated by cross-flow filtration and diafiltration prior topurification.

(iv) Tagged Protein Purification

Recombinant tagged HER3 proteins (e.g., TAG-HER3) were purified bycollecting the cell culture supernatant and concentrating 10-fold bycross-flow filtration with a 10 kDa cut off filter (Fresenius). Ananti-TAG column was prepared by coupling an anti-TAG monoclonal antibodyto CNBr activated Sepharose 4B at a final ratio of 10 mg antibody per mLof resin. Concentrated supernatant was applied to a 35 ml anti-Tagcolumn at a flow rate of 1-2 mL/minute. After base-line washing withPBS, bound material was eluted with 100 mM glycine (pH 2.7), neutralizedand sterile filtered. Protein concentrations were determined bymeasuring the absorbance at 280 nm and converting using a theoreticalfactor of 0.66 AU/mg. The purified protein was finally characterized bySDS-PAGE, N-terminal sequencing and LC-MS.

(v) Fc Tag Purification

Concentrated cell culture supernatant was applied to a 50 ml Protein ASepharose Fast Flow column at a flow rate of 1 ml/min. After baselinewashing with PBS, the column was washed with 10 column volumes of 10 mMNaH₂PO₄/30% (v/v) Isopropanol, pH 7.3 followed by 5 column volumes ofPBS. Finally, bound material was eluted with 50 mM Citrate/140 mM NaCl(pH 2.7), neutralized and sterile filtered.

(vi) HuCAL GOLD® OR PLATINUM® Pannings

For the selection of antibodies recognizing human HER3 multiple panningstrategies were employed. Therapeutic antibodies against human HER3protein were generated by selection of clones having high bindingaffinities, using as the source of antibody variant proteins acommercially available phage display library, the MorphoSys HuCAL GOLD®or Platinum® library. The phagemid library is based on the HuCAL®concept (Knappik et al., (2000) J Mol Biol 296:57-86) and employs theCysDisplay® technology for displaying the Fab on the phage surface(WO01/05950 to Lohning).

For the isolation of anti-HER3 antibodies, standard as well as RapMATpanning strategies were performed using solid phase, solution, wholecell and differential whole cell panning approaches.

(vii) Solid Phase Panning

To identify anti-HER3 antibodies a variety of solid phase panningstrategies were performed using differing recombinant HER3 proteins. Toperform each round of solid phase panning, Maxisorp plates (Nunc) werecoated with HER3 protein. Tagged proteins were either captured usingplates previously coated with anti-Fc (goat or mouse anti-human IgG,Jackson Immuno Research), anti-Tag antibody or via passive adsorption.The coated plates were washed with PBS and blocked. Coated plates werewashed twice with PBS prior to the addition of HuCAL GOLD® or Platinum®phage-antibodies for 2 hours at room temperature on a shaker. Boundphages were eluted were added to E. coli TG-1 and incubated for phageinfection. Subsequently infected bacteria were isolated and plated onagar plates. Colonies were scraped off the plates and phages wererescued and amplified. Each HER3 panning strategy comprised ofindividual rounds of panning and contained unique antigens, antigenconcentrations and washing stringency.

(viii) Solution Phase Panning

Each round of solution phase panning was performed using variousbiotinylated recombinant HER3 proteins in the presence or absence ofneuregulin 1-31 (R&D Systems). Proteins were biotinylated using theEZ-link sulfo-NHS-LC biotinylation kit (Pierce) according to themanufacturers instructions. 800 μl of Streptavidin linked magnetic beads(Dynabeads, Dynal) were washed once with PBS and blocked overnight withChemiblocker (Chemicon). HuCAL GOLD® or Platinum® phage-antibodies andthe appropriate biotinylated HER3 were incubated in a reaction tube.Streptavidin magnetic beads were added for 20 minutes and were collectedwith a magnetic particle separator (Dynal). Bound phages were elutedfrom the Dynabeads by adding DTT containing buffer to each tube andadded to E. coli TG-1. Phage infection was performed in an identicalmanner to that described in solid phase panning. Each HER3 panningstrategy comprised of individual rounds of panning and contained uniqueantigens, antigen concentrations and washing stringency. In order toisolate antibodies targeting a specific epitope, competition panningswere performed. In these panning strategies HER3 was incubated andpre-blocked with a reference antibody prior to addition of HuCAL GOLD®or Platinum® phage-antibodies. As an alternative strategy referenceantibodies were used to specifically elute phage-antibodies complexedwith HER3.

(ix) Cell Based Panning

For cell pannings, HuCAL GOLD® or Platinum® phage-antibodies wereincubated with approximately 10⁷ cells on a rotator for 2 hours at roomtemperature, followed by centrifugation. The cell pellet was isolatedphages were eluted from the cells The supernatant was collected andadded to E. coli TG-1 culture continued by the process described above.Two cell based strategies were employed to identify anti-HER3antibodies:

-   -   a) Whole cell panning: In this strategy a variety of intact cell        lines were used as the antigens.    -   b) Differential whole cell panning: In this strategy the        antigens sequentially consisted of cells and recombinant HER3        proteins. The cell based pannings were performed as described        above whilst solid phase panning protocols were employed when        recombinant proteins were utilized as antigens. The washes were        conducted using PBS (2-3×) and PBST (2-3×).

(x) RapMAT™ Library Generation and Pannings

In order to increase antibody binding affinity whilst maintaininglibrary diversity the second round output of both solution and solidphase pannings were entered into the RapMAT™ process whilst the thirdround output of the whole cell and differential whole cell panningstrategies were entered (Prassler et al., (2009) Immunotherapy; 1:571-583). RapMAT™ libraries were generated by sub-cloning Fab-encodinginserts of phages selected via panning into the display vectorpMORPH®25_bla_LHC and were further digested to either generateH-CDR2RapMAT™ libraries and L-CDR3RapMAT™ libraries by using specificrestriction enzymes. The inserts were replaced with TRIM maturationcassettes (Virnekas et al., (1994) Nucleic Acids Research 22:5600-5607)for H-CDR2 or L-CDR3 according to pool composition. Library sizes wereestimated to range between 8×10⁶-1×10⁸ clones. RapMAT antibody-phagewere produced and subjected to two further rounds of solution, solidphase or cell based panning using the experimental methods describedpreviously.

This extensive panning strategy, involving an iterative refinement oflibrary design was specifically developed to bias screening away frompure ligand-competitive antibodies by including ligand-blockingantibodies directly in the pannings. Secondly, the FAB to IgG conversionprocess was adapted to maximize the recovery of candidate clones andensure that all selective binders were profiled in functional assays.From 44 initial pannings, yielding around 28 families of specific Her3binding antibodies, only three antibody families displayed the desiredproperty of blocking both ligand-dependent and independent signaltransduction. Family A that binds isolated domains 1-2 and 2 of Her3.Family B that binds isolated domains 3-4, but not 4 alone; and family C,which binds domain 3.

Example 2 Transient Expression of Anti-HER3 IgG's

Suspension adapted HEK293-6E cells were cultivated in a BioWave20. Thecells were transiently transfected with the relevant sterile DNA:PEI-MIX and further cultivated. After transfection, cells were removedby crossflow filtration using Fresenius filters. The cell free materialwas concentrated with crossflow filtration using a cut off filter(Fresenius) and the concentrate was sterile filtered through a stericupfilter. The sterile supernatant was stored at 4° C.

Example 3 Purification of anti-HER3 IgG

The purification of IgG was performed on a ÄKTA 100 explorer Airchromatography system in a cooling cabinet, using a XK16/20 column with25 mL of self-packed MabSelect SuRe resin (all GE Healthcare). All flowrates were 3.5 mL/min, except for loading, at a pressure limit of 5 bar.The column was equilibrated with 3 column volumes of PBS prior toloading the filtered fermentation supernatant. The column was washedwith PBS. IgG was eluted with a pH gradient, starting at citrate/NaCl(pH 4.5), going linearly down to citrate/NaCl (pH 2.5), followed by aconstant step of the same pH 2.5 buffer. The IgG containing fractionswere pooled and immediately neutralized and sterile filtered (MilliporeSteriflip, 0.22 um). OD₂₈₀ was measured and the protein concentrationcalculated based on the sequence data. The pools were separately testedfor aggregation (SEC-MALS) and purity (SDS-PAGE and MS).

Example 4 Expression and Purification of HuCAL®-Fab Antibodies in E.coli

Expression of Fab fragments encoded by pMORPH®X9_Fab_MH in TG-1 cellswas carried out in shaker flask cultures using YT medium supplementedwith chloramphenicol. Cultures were shaken until the OD600 nm reached0.5. Expression was induced by addition of IPTG(isopropyl-β-D-thiogalactopyranoside). Cells were disrupted usinglysozyme. His₆-tagged Fab (‘His₆’ disclosed as SEQ ID NO: 702) fragmentswere isolated via IMAC (Bio-Rad). Buffer exchange to 1× Dulbecco's PBS(pH 7.2) was performed using PD10 columns. Samples were sterilefiltered. Protein concentrations were determined byUV-spectrophotometry. The purity of the samples was analyzed indenaturing, reducing 15% SDS-PAGE. The homogeneity of Fab preparationswas determined in native state by size exclusion chromatography (HP-SEC)with calibration standards.

Example 5 HER3 Antibody Affinity (K_(D)) Measurements by SolutionEquilibrium Titration (SET)

Affinity determination in solution was essentially performed aspreviously described (Friguet et al., (1985) J Immunol Methods77:305-19). In order to improve the sensitivity and accuracy of the SETmethod, it was transferred from classical ELISA to ECL based technology(Haenel et al., (2005) Anal biochem 339:182-84).

Unlabeled HER3-Tag (human, rat, mouse or cyno) described previously wasused for affinity determination by SET.

The data was evaluated with XLfit software (ID Business Solutions)applying customized fitting models. For K_(D) determination of each IgGthe following model was used (modified according to Piehler, et al(Piehler et al., (1997) J Immunol Methods 201:189-206).

$y = {\frac{2\; B_{\max}}{\lbrack{IgG}\rbrack}\left( {\frac{\lbrack{IgG}\rbrack}{2} - \frac{\left( {\frac{x + \lbrack{IgG}\rbrack + K_{D}}{2} - \sqrt{\frac{\left( {x + \lbrack{IgG}\rbrack + K_{D}} \right)^{2}}{4} - {x\lbrack{IgG}\rbrack}}} \right)^{2}}{2\lbrack{IgG}\rbrack}} \right)}$

[IgG]: applied total IgG concentrationx: applied total soluble antigen concentration (binding sites)B_(max): maximal signal of IgG without antigenK_(D): affinity

Example 6 Antibody Cell Binding Determination by FACS

The binding of antibodies to endogenous human antigen expressed on humancancer cells was accessed by FACS. In order to determine antibody EC₅₀values SK-Br-3 cells were harvested with accutase and diluted to 1×10⁶cells/mL in FACS buffer (PBS/3% FBS/0.2% NaN₃). 1×10⁵ cells/well wereadded to each well of a 96-well plate (Nunc) and centrifuged at 210 gfor 5 minutes at 4° C. before removing the supernatant. Serial dilutionsof test antibodies (diluted in 1:4 dilution steps with FACS buffer) wereadded to the pelleted cells and incubated for 1 hour on ice. The cellswere washed and pelleted three times with 100 L FACS buffer. PEconjugated goat anti-human IgG (Jackson ImmunoResearch) diluted 1/200with FACS buffer were added to the cells and incubated on ice for 1hour. Additional washing steps were performed three times with 100 μLFACS buffer followed by centrifugation steps at 210 g for 5 minutes at4° C. Finally, cells were resuspended in 200 μL FACS buffer andfluorescence values were measured with a FACSArray (BD Biosciences). Theamount of cell surface bound anti-HER3 antibody was assessed bymeasuring the mean channel fluorescence.

Example 7 HER3Domain Binding

96-well Maxisorp plates (Nunc) were coated overnight with 200 ng of theappropriate recombinant human protein (HER3-Tag, D1-2-Tag, D2-Tag,D3-4-Tag, D4-Tag, and a tagged irrelevant control protein). All wellswere then washed with PBS/0.1% Tween-20, blocked with PBS/1% BSA/0.1%Tween-20 and washed with PBS/0.1% Tween-20. Anti-HER3 antibodies wereadded to the relevant wells up to a final concentration of 10 μg/mL andincubated at room temperature. Plates were washed with PBS/0.1% Tween-20prior to the addition of the appropriate peroxidase linked detectionantibody diluted 1/10000 in PBS/1% BSA/0.1% Tween-20. The detectionantibodies used were goat anti-mouse (Pierce, 31432), rabbit anti-goat(Pierce, 31402) and goat anti-human (Pierce, 31412). Plates wereincubated at room temperature before washing with PBS/0.1% Tween-20. 100μl TMB (3,3′,5,5′ tetramethyl benzidine) substrate solution (BioFx) wasadded to all wells before stopping the reaction with 50 μl 12.5% H₂SO₄.The extent of HER3 antibody binding to each recombinant protein wasdetermined by measuring the OD₄₅₀ using a SpectraMax plate reader(Molecular Devices). Where appropriate, dose response curves wereanalyzed using Graphpad Prism.

Example 8 X-Ray Crystallographic Structure Determination of the HumanHER3/MOR12604 Fab Complex

The present example presents the crystal structure of HER3 bound to theFab fragment of MOR12604 determined at 3.38 Å resolution. Tagged humanHER3 extracellular domainwas further purified on a HiLoad 26/60 Superdex200 PrepGrade column (GE Healthcare) equilibrated in PBS (pH 7.3).MOR12604 Fab was expressed in E. coli and purified as previouslydescribed. HER3/MOR12604-Fab complex was prepared by mixing excessMOR12604 Fab with tagged HER3 in a molar ratio of 2:1 (concentrationestimated by LCUV methods) and purifying the complex on a Superdex 20010/300 column (GE Healthcare) equilibrated in 25 mM Tris (pH 7.5), 150mM NaCl. Peak fractions were analyzed by SDS-PAGE and LCMS. Fractionscontaining both HER3 and Fab in an approximate equimolar ratio werepooled and concentrated to 10 mg/ml. HER3/MOR12604 crystals were grownat 293K by sitting drop vapor diffusion from drops containing 150 nlHER3/MOR12604 complex and 150 nl of reservoir solution (200 mMdi-potassium hydrogen phosphate and 20% PEG 3350). Crystals weretransferred to 200 mM di-potassium hydrogen phosphate, 25% PEG 3350 and15% glycerol and flash cooled in liquid nitrogen.

Data were collected at beamline 17-ID at the Advanced Photon Source(Argonne National Laboratory). HER3/MOR12604 Fab complex data wereprocessed and scaled at 3.38 Å using autoPROC (Global Phasing, LTD) inspace group P2₁2₁2₁ with cell dimensions a=56.15, b=174.71, c=186.64 Å,with good statistics. The HER3/MOR12604 Fab structure was solved bymolecular replacement using Phaser (McCoy et al., (2007) J. Appl. Cryst.40:658-674) with the published HER3 ECD structure lmb6 and a proprietaryFab as search models. The final model, which contains 1 molecule of theHER3/MOR12604 Fab complex per asymmetric unit, was built in COOT (Emsley& Cowtan (2004) Acta Cryst. 60:2126-2132) and refined to R and Rfreevalues of 19.9 and 23.3%, respectively, with an rmsd of 0.008 Å and1.19° for bond lengths and bond angles, respectively, using BUSTER(Global Phasing, LTD). Residues of HER3 that contain atoms within 5 Å ofany atom in MOR12604 Fab as identified in PyMOL (Schrödinger, LLC) arelisted in Tables 5 and 6.

Example 9 Phospho-HER3 In Vitro Cell Assays

MCF-7 cells were routinely maintained in DMEM/F 12, 15 mM HEPES,L-glutamine, 10% FBS, BT474 in DMEM, 10% FBS and SK-Br-3 in McCoy's 5a,10% FBS, 1.5 mM L-glutamine. Sub-confluent cells were trypsinized,washed with PBS and diluted to 5×10⁵ cells/mL. 100 μL of cell suspensionwas then added to each well of a 96-well flat bottomed plate (Nunc) togive a final density of 5×10⁴ cells/well. MCF7 cells were allowed toattach for approximately 3 hours before the media was exchanged forstarvation media containing 0.5% FBS. All plates were then incubatedovernight at 37° C. prior to treatment with the appropriateconcentration of HER3 antibodies for 80 minutes at 37° C. MCF7 cellswere treated with 50 ng/mL NRG1 for the final 20 minutes to stimulateHER3 and AKT phosphorylation whilst BT474/SK-Br-3 cells required noadditional stimulation. All media was gently aspirated and the cellswashed with ice-cold PBS containing 1 mM CaCl₂ and 0.5 mM MgCl₂ (Gibco).The cells were lysed by adding 50 L ice-cold lysis buffer (20 mM Tris(pH8.0)/137 mM NaCl/10% Glycerol/2 mM EDTA/1% NP-40/1 mM sodiumorthovanadate/1× Phospho-Stop/1× Complete mini protease inhibitors(Roche)/0.1 mM PMSF) and incubated on ice with shaking for 30 minutes.Lysates were then collected and spun at 1800 g for 15 minutes at 4° C.to remove cell debris.

HER3 capture plates were generated using a carbon plate (MesoscaleDiscovery) coated overnight at 4° C. with 20 μL of 4 μg/mL MAB3481capture antibody (R&D Systems) diluted in PBS and subsequently blockedwith 3% bovine serum albumin in 1× Tris buffer (MesoscaleDiscovery)/0.1% Tween-20. HER3 was captured by adding the appropriateamount of lysate and incubating the plate at room temperature for onehour with shaking before the lysate was aspirated and the wells washedwith 1× Tris buffer (Mesoscale Discovery)/0.1% Tween-20. PhosphorylatedHER3 was detected using 1:8000 anti-pY1197 antibody (Cell Signaling)prepared in 3% milk/1× Tris/0.1% Tween-20 by incubating with shaking atroom temperature for 1 hour. The wells were washed four times with 1×Tris/0.1% Tween-20 and phosphorylated proteins were detected byincubating with S-Tag labelled goat anti-rabbit Ab (#R32AB) diluted in3% blocking buffer for one hour at room temperature. Each well wasaspirated and washed four times with 1× Tris/0.1% Tween-20 before adding20 μL of Read buffer T with surfactant (Mesoscale Discovery) and thesignal quantified using a Mesoscale Sector Imager.

Example 10 Phospho-Akt (S473) In Vitro Cell Assays

Sub-confluent MCF7, SK-Br-3 and BT-474 cells were grown in completemedia were harvested with accutase (PAA Laboratories) and resuspended inthe appropriate growth media at a final concentration of 5×10⁵ cells/mL.100 μL of cell suspension was then added to each well of a 96-well flatbottomed plate (Nunc) to yield a final density of 5×10⁴ cells/well. MCF7cells were allowed to attach for approximately 3 hours before the mediawas exchanged for starvation media containing 0.5% FBS. All plates werethen incubated overnight at 37° C. prior to treatment with theappropriate concentration of HER3 antibodies for 80 minutes at 37° C.MCF7 cells were treated with 50 ng/mL NRG1 for the final 20 minutes tostimulate HER3 and AKT phosphorylation whilst SK-Br-3 cells required noadditional stimulation. All media was gently aspirated and the cellswashed with ice-cold PBS containing 1 mM CaCl₂ and 0.5 mM MgCl₂ (Gibco).The cells were lysed by adding 50 μL ice-cold lysis buffer (20 mM Tris(pH8.0)/137 mM NaCl/10% Glycerol/2 mM EDTA/1% NP-40/1 mM sodiumorthovanadate/Aprotinin (10 μg/mL)/Leupeptin (10 μg/mL)) and incubatedon ice with shaking for 30 minutes. Lysates were then collected and spunat 1800 g for 15 minutes at 4° C. to remove cell debris. 20 μL of lysatewas added to a multi-spot 384-well Phospho-Akt carbon plate (MesoscaleDiscovery) that had previously been blocked with 3% BSA/1× Tris/0.1%Tween-20. The plate was incubated at room temperature for two hours withshaking before the lysate was aspirated and the wells washed four timeswith 1× Tris buffer (Mesoscale Discovery)/0.1% Tween-20. PhosphorylatedAkt was detected using 20 μL of SULFO-TAG anti-phospho-Akt (S473)antibody (Mesoscale Discovery) diluted 50-fold in 1% BSA/1× Tris/0.1%Tween-20 by incubating with shaking at room temperature for 2 hours. Thewells were washed four times with 1× Tris/0.1% Tween-20 before adding 20μL of Read buffer T with surfactant (Mesoscale Discovery) and the signalquantified using a Mesoscale Sector Imager.

Example 11 Cell-Line Proliferation Assays

SK-Br-3 cells were routinely cultured in McCoy's 5A medium modified,supplemented with 10% fetal bovine serum and BT-474 cells were culturedin DMEM supplemented with 10% FBS. Sub-confluent cells were trypsinized,washed with PBS, diluted to 5×10⁴ cells/mL with growth media and platedin 96-well clear bottom black plates (Costar 3904) at a density of 5000cells/well. The cells were incubated overnight at 37° C. before addingthe appropriate concentration of HER3 antibody (typical finalconcentrations of 10 or 1 μg/mL). The plates were returned to theincubator for 6 days before assessing cell viability using CellTiter-Glo(Promega). 100 L of CellTiter-Glo solution was added to each well andincubated at room temperature with gentle shaking for 10 minutes. Theamount of luminescence was determined using a SpectraMax plate reader(Molecular Devices). The extent of growth inhibition obtained with eachantibody was calculated by comparing the luminscence values obtainedwith each HER3 antibody to a standard isotype control antibody.

For proliferation assays MCF-7 cells were routinely cultured in DMEM/F12(1:1) containing 4 mM L-Glutamine/15 mM HEPES/10% FBS. Sub-confluentcells were trypsinized, washed with PBS and diluted to 1×10⁵ cells/mLwith DMEM/F12 (1:1) containing 4 mM L-Glutamine/15 mM HEPES/10 μg/mLHuman Transferrin/0.2% BSA. Cells were plated in 96-well clear bottomblack plates (Costar) at a density of 5000 cells/well. The appropriateconcentration of HER3 antibody (typical final concentrations of 10 or 1μg/mL) was then added. 10 ng/mL of NRG1-β1 EGF domain (R&D Systems) wasalso added to the appropriate wells to stimulate cell growth. The plateswere returned to the incubator for 6 days before assessing cellviability using CellTiter-Glo (Promega). The extent of growth inhibitionobtained with each antibody was calculated by subtracting the background(no neuregulin) luminscence values and comparing the resulting valuesobtained with each anti-HER3 antibody to a standard isotype controlantibody.

Example 12 In Vivo BxPC3 Efficacy Studies

BxPC3 cells were cultured in RPMI-1640 medium containing 10%heat-inactivated fetal bovine serum without antibiotics until the timeof implantation.

Female athymic nu/nu Balb/C mice (Harlan Laboratories) were implantedsubcutaneously with 10×10⁶ cells in a mixture of 50% phosphate bufferedsaline with 50% matrigel. The total injection volume containing cells insuspension was 200 μL. Once tumors had reached approximately 200 mm3 insize, animals were enrolled in the efficacy study. In general, a totalof 10 animals per group were enrolled in studies. Animals were excludedfrom enrollment if they exhibited unusual tumor growth characteristicsprior to enrollment.

Animals were dosed intravenously via lateral tail vein injection.Animals were on a 20 mg/kg, twice weekly schedule for the duration ofthe study. Tumor volume and T/C values were calculated as detailed forthe BT-474 studies.

Example 13 In Vivo BT474 Efficacy Studies

BT-474 cells were cultured in DMEM containing 10% heat-inactivated fetalbovine serum without antibiotics until the time of implantation.

One day before cell inoculation, female athymic nu/nu Balb/C mice(Harlan Laboratories) were implanted subcutaneously with a sustainedrelease 17β-estradiol pellet (Innovative Research of America) tomaintain serum estrogen levels. One day after 17β-estradiol pelletimplantation, 5×10⁶ cells were injected orthotopically into the 4thmammary fatpad in a suspension containing 50% phenol red-free matrigel(BD Biosciences) in Hank's balanced salt solution. The total injectionvolume containing cells in suspension was 200 μL. 20 days following cellimplantation animals with a tumor volume of approximately 200 mm³ wereenrolled in the efficacy study. In general, a total of 10 animals pergroup were enrolled in efficacy studies.

For single-agent studies, animals were dosed intravenously via lateraltail vein injection with control IgG or MOR12606 or MOR13655. Animalswere on a 20 mg/kg, twice weekly dosing schedule for the duration of thestudy. For combination studies, animals were dosed twice weekly at 20mg/kg for both MOR10703 and MOR12606. For the duration of the studies,tumor volume was measured by calipering twice per week. Percenttreatment/control (T/C) values were calculated using the followingformula:

% T/C=100×ΔT/ΔC if ΔT>0

where:T=mean tumor volume of the drug-treated group on the final day of thestudy;ΔT=mean tumor volume of the drug-treated group on the final day of thestudy−mean tumor volume of the drug-treated group on initial day ofdosing;C=mean tumor volume of the control group on the final day of the study;andΔC=mean tumor volume of the control group on the final day of thestudy−mean tumor volume of the control group on initial day of dosing.

Body weight was measured twice per week and dose was body weightadjusted. The % change in body weight was calculated as(BWcurrent−BWinitial)/(BWinitial)×100. Data is presented as percent bodyweight change from the day of treatment initiation.

All data were expressed as mean±standard error of the mean (SEM). Deltatumor volume and body weight were used for statistical analysis. Betweengroups comparisons were carried out using a one-way ANOVA followed by apost hoc Tukey. For all statistical evaluations the level ofsignificance was set at p<0.05. Significance compared to the vehiclecontrol group is reported.

Results and Discussion

Collectively, these results show that a class of antibodies bind toamino acid residues within domain 3 or 4. Binding of these antibodiesinhibits both ligand-dependent and ligand-independent signaling.

(i) Affinity Determination

Antibody affinity was determined by solution equilibrium titration (SET)as described above. The results are summarized in Table 3 and exampletitration curves for MOR12615 and MOR12604 are contained in FIG. 1. Thedata indicate that a number of antibodies were identified that tightlybound human HER3.

TABLE 3 K_(D) values of anti-HER3 IgGs as determined by solutionequilibrium titration (SET). SET K_(D) (pM) hu cy mu ra MOR# HER3-TagHER3-Tag HER3-Tag HER3-Tag MOR12514 970 1400 2400 nd MOR12515 870 7201500 nd MOR12516 1800 3600 3900 nd MOR12615 102 257 336 310 MOR12920 ndnd nd nd MOR12921 150 600 560 690 MOR12922 nd nd nd nd MOR13654 110 ndnd nd MOR13655 66 nd nd nd MOR13656 nd nd nd Nd MOR13657 87 nd nd ndMOR13658 27 nd nd nd MOR13659 nd nd nd nd MOR13660 nd nd nd nd MOR13661nd nd nd nd MOR13662 nd nd nd nd MOR13663 nd nd nd nd MOR13664 nd nd ndnd MOR13665 nd nd nd nd MOR13666 150 nd nd nd MOR13667 nd nd nd ndMOR13668 nd nd nd nd MOR13669 nd nd nd nd MOR13670 nd nd nd nd MOR14537210 140 220 285 MOR14538 45 26 23 51 MOR12603 2000 6100 4100 11000MOR12604 1100 2200 1900 5200 MOR12605 1800 2900 2300 9600 MOR12606 15002600 1400 8100 MOR14533 640 2950 2000 9650 MOR14534 2150 6350 4000 30000Hu (human), Cy (cynomolgus monkey), Mu (murine) and ra (rat), nd (notdetermined).

(ii) SK-Br-3 Cell EC₅₀ Determination

The ability of the identified antibodies to bind HER3 expressing cellswas determined by calculating EC₅₀ values for their binding to the HER2amplified cell line SK-Br-3 (see FIG. 2, Table 4).

TABLE 4 FACS EC₅₀ values of anti-HER3 IgG on cells. MOR# SK-Br-3 FACSEC₅₀ (pM) 14537 179 14538 279 14533 42 14534 28(iii) HER3Domain Binding

A subset of anti-HER3 antibodies were characterized for their ability tobind the various extracellular domains of human HER3 in an ELISA assay.To achieve this, the extracellular domain of HER3 was divided into itsfour constitutive domains and various combinations of these domains werecloned, expressed and purified as independent proteins as describedabove. Using this strategy the following domains were successfullygenerated as soluble proteins: domains 1 and 2 (D1-2), domain 2 (D2),domains 3 and 4 (D3-4) and domain 4 (D4). The integrity of each isolateddomain was previously confirmed using a panel of internally generatedantibodies as positive controls.

As shown in FIG. 3, MOR12615 and MOR12604 were observed to successfullybind the HER3 extracellular domain and isolated D3-4 protein. No bindingwas observed with D1-2 or D2 protein. This binding data suggests thatthese antibodies recognize an epitope primarily contained within domains3 or 4. Interestingly, MOR12604 could bind isolated D3 proteinsuggesting that its epitope could be further refined to residues withindomain 3. Since MOR12615 and MOR12604 are representative members of twodistinct families of anti-HER3 antibodies based upon their hCDR3sequences antibodies MOR12514, MOR12515, MOR12516, MOR12615, MOR12920,MOR12921, MOR12922, MOR13654, MOR13655, MOR13656, MOR13657, MOR13658,MOR13659, MOR13660, MOR13661, MOR13662, MOR13663, MOR13664, MOR13665,MOR13666, MOR13667, MOR13668, MOR13669, MOR13670, MOR14537 and MOR14538can be classed as D3-4 binder. Antibodies MOR12603, MOR12604, MOR12605,MOR12606, MOR14533 and MOR14534 can be classed as D3 binders.

(Iv) HER3/MOR12604 Crystal Structure

The 3.38 Å resolution x-ray crystal structure of MOR12604 Fab fragmentbound to the HER3 extracellular domain was solved to further define theHER3 epitope that is recognized by this family of related antibodies(see FIG. 4). Overlay of the MOR12604/HER3 crystal structure withpublished HER3 crystal structures suggested that HER3 bound by MOR12604is in the tethered (inactive) conformation (see FIG. 4B). Thisconformation is characterized by a significant interaction interfacebetween domains 2 and 4 mediated by a (3-hairpin dimerization loop indomain 2. The observed conformation of HER3 is similar to thatpreviously described by Cho et al. (Cho & Leahy, (2002), Science297:1330-1333) who published the crystal structure of the HER3extra-cellular domain in the absence of neuregulin. Since neuregulin canactivate HER3, the tethered conformation of HER3 is presumed to beinactive. Similar tethered conformations have also been observed whenthe related EGFR family members HER4 (Bouyain et al., (2005) Proc. Natl.Acad. Sci. USA, 102:15024-15029) and HER1 (Ferguson et al., (2003)Molec. Cell 11:507-517) have been crystallized.

The spatial relationships between domains 1 to 4 of HER3 in the inactive(tethered) state are significantly different from that of the extended(active) state. This finding is based upon the crystal structures of therelated EGFR family members HER2 and ligand-bound HER1 (Cho et al.,(2003) Nature 421:756-760; Ogiso et al., (2002) Cell 110:775-787;Garrett et al., (2002) Cell 110:763-773) both of which are in anextended (active) state. In the extended state, the domain 2β-hairpindimerization loop is released from its inhibitory interaction with 4 andis thus free to interact with its dimerization partner proteins. Thus,the domain 2 β-hairpin dimerization loop is functionally important bothin maintaining the tethered (inactive) state and in mediatingdimerization of EGF receptors in the extended state, leading toactivation of the intracellular kinase domain.

In the crystal structure, electron density for MOR12604 Fab, HER3 domain3, HER3 domain 4 and a portion of domain 2 (residues 261-278) includingthe β-hairpin dimerization loop were all well defined. Weak or noelectron density was observed for HER3 residues 20-260 and 279-303 whichare located in domain 1 and domain 2, suggesting that when HER3 is boundby MOR12604 it retains some degree of flexibility. This finding isconsistent with a comparison of other crystal structures of HER3 aloneand bound to various Fab fragments that showed slight differences inrelative domain positioning within the tethered state.

The crystal structure also revealed that the HER3 epitope recognized byMOR12604 is a non-linear epitope that includes residues from domain 3(see FIG. 4, Tables 5 and 6). The HER3 epitope recognized by this familyof highly related antibodies can therefore be defined as:

Domain 3: residues 335-342, 362-376, 398, 400, 424-428, 431, 433-434 and455.

The MOR12604 binding surface can be further subdivided into two surfaceshighlighted as solid and dashed circles in FIG. 4D:

Surface A: residues 362-376

Surface B: residues 335-342, 398, 400, 424-428, 431, 433-434 and 455

Surface A or Surface B contribute approximately the same surface area tothe overall HER3/12604 interface (Surface A—640 Å², Surface B—546 Å²).

Interestingly, MOR12604 binding to domain 3 resulted in a significantconformational change in the loop defined by HER3 residues 371-377. Thisconformation of this loop is different from other published HER3structures thus suggesting that it is induced by MOR12604 binding. TheMOR12604 epitope determined from the crystal structure is consistentwith our ELISA domain binding data where MOR12604 was determined to bindisolated D3 protein. Furthermore, comparison of the MOR12604 epitopewith the EGFR residues contacted by TGFα highlighted a high degree ofoverlap (Garrett et al., (2002) Cell 110:763-773). Since neuregulin isthought to interact with HER3 in a similar manner to TGFα/EGFR it ishighly likely that MOR12604 will prevent ligand binding thus blockingneuregulin induced HER3 activation.

Binding within domain 3 by MOR12604 would suggest that MOR12604 couldfunction by any (or a combination) of the following mechanisms:

by blocking HER3 residues required for ligand binding

by preventing HER3 adopting the active conformation due to sterichindrance between the antibody and domains of HER3

by preventing HER3 adopting the active conformation by reducing thedegree of flexibility in HER3 hinge regions (e.g. domain 3)

by inducing a conformational change in domain 3 loop 371-377 thatprevents HER3 from transitioning to the open conformation

by destabilizing HER3 such that it is prone to degradation

by acting as a partial agonist to accelerate the down regulation of HER3

by inhibiting dimerization with a binding partner

by each arm of MOR12604 binding a molecule of HER3 such that theantibody generates an un-natural HER3 dimer that is either prone toproteolytic degradation or cannot dimerize with other receptor tyrosinekinases

TABLE 5 Interactions between MOR12604 Fab heavy chain and human HER3.Fab VH residues are numbered based upon their linear amino acid sequence(SEQ ID NO: 1). HER3 residues are numbered based upon NP_001973. HER3residues shown have at least one atom within 5 Å of an atom in theMOR12604 Fab. MOR12604 Fab Human HER3 Residue Number Chain ResidueNumber Domain GLN 1 H PRO 372 3 TRP 373 3 HIS 374 3 LYS 375 3 VAL 2 HPRO 372 3 TRP 373 3 LEU 4 H TRP 373 3 ALA 24 H TRP 373 3 THR 28 H TRP373 3 PHE 29 H TRP 373 3 TYR 32 H GLY 370 3 ASP 371 3 PRO 372 3 TRP 3733 ILE 34 H TRP 373 3 ARG 98 H ASP 371 3 TRP 373 3 TRP 100 H ILE 365 3THR 366 3 ASN 369 3 GLY 370 3 ASP 371 3 PRO 101 H ILE 365 3 THR 366 3TYR 102 H ILE 365 3 GLN 400 3 LYS 434 3 ASP 106 H ASP 371 3 PHE 107 HASP 371 3 TRP 373 3 HIS 374 3

TABLE 6 Interactions between MOR12604 Fab light chain and human HER3.Fab VL residues are numbered based upon their linear amino acid sequence(SEQ ID NO: 1). HER3 residues are numbered based upon NP_001973. HER3residues shown have at least one atom within 5 Å of an atom in theMOR12604 Fab. MOR12604 Fab Human HER3 Residue Number Chain ResidueNumber Domain VAL 30 L MET 433 3 TYR 455 3 PHE 31 L ASN 425 3 PHE 428 3LEU 431 3 MET 433 3 TYR 455 3 TYR 49 L LEU 364 3 ILE 365 3 THR 366 3 ASP50 L GLN 400 3 TYR 424 3 LYS 434 3 ALA 51 L ASN 425 3 SER 52 L TYR 424 3ASN 425 3 ASN 53 L ASP 362 3 LEU 364 3 ASN 398 3 GLN 400 3 TYR 424 3 ARG54 L GLY 335 3 SER 336 3 GLY 337 3 SER 338 3 PHE 340 3 GLN 341 3 LEU 3643 THR 366 3 ALA 55 L GLN 341 3 THR 56 L GLN 341 3 THR 366 3 HIS 374 3THR 56 L ILE 376 3 GLY 57 L GLN 341 3 VAL 58 L GLN 341 3 ALA 60 L GLY337 3 SER 338 3 GLY 64 L ASN 425 3 SER 65 L ASN 425 3 ARG 426 3 GLY 66 LASN 425 3 ARG 426 3 SER 67 L ASN 425 3 ARG 426 3 LYS 91 L LYS 434 3

(v) Inhibition of Cell Signaling

To ascertain the effect of anti-HER3 antibodies upon ligand dependentHER3 activity MCF7 cells were incubated with IgG prior to stimulationwith neuregulin. Example inhibition curves are illustrated in FIG. 5 andsummarized in Table 7. The effect of anti-HER3 antibodies uponHER2-mediated HER3 activation was also studied using the HER2 amplifiedcell lines SK-Br-3 and BT474 (FIG. 6, FIG. 7, and Table 7).

TABLE 7 pHER3 IC₅₀ and extent of inhibition values of anti-HER3 IgG inMCF7, BT474 and SK-Br-3 cells. MCF7 pHER3 SK-Br-3 pHER3 BT474 pHER3 IC₅₀% IC₅₀ % IC₅₀ % MOR# (pM) inhibition (pM) inhibition (pM) inhibitionMOR12514 435 67 223 77 707 70 MOR12515 674 71 278 76 365 71 MOR12516 59062 1873 74 nd 63 MOR12615 447 75 179 71 421 56 MOR12920 3066 66 851 572021 57 MOR12921 1230 79 252 68 418 65 MOR12922 788 62 81 64 702 58MOR13654 331 77 182 69 195 61 MOR13655 149 80 90 69 19 61 MOR13656 50473 86 60 nd nd MOR13657 283 75 142 71 372 63 MOR13658 459 83 347 74 57167 MOR13659 505 66 277 51 nd nd MOR13660 533 49 188 54 nd nd MOR13661649 55 421 55 nd nd MOR13662 550 52 331 56 nd nd MOR13663 449 58 290 56nd nd MOR13664 480 55 388 57 nd nd MOR13665 795 62 546 59 nd nd MOR13666168 73 166 69 420 65 MOR13667 603 72 267 59 nd nd MOR13668 1640 77 65758 nd nd MOR13669 nd 66 743 58 nd nd MOR13670 643 69 730 60 nd ndMOR14537 200 73 97 69 nd nd MOR14538 615 83 263 71 nd nd MOR12603 11 7718 74 79 70 MOR12604 57 79 29 71 142 62 MOR12605 318 89 7 73 1486 64MOR12606 34 87 25 75 108 73 MOR14533 50 67 20 68 nd nd MOR14534 16 71 1063 nd nd

To determine whether inhibition of HER3 activity impacted downstreamcell signaling, Akt, phosphorylation was measured in NRG stimulated MCF7cells and HER2 amplified SK-Br-3/BT474 cells following treatment withanti-HER3 antibodies (see FIG. 5, FIG. 6, and Table 8)

TABLE 8 pAkt (S⁴⁷³) IC₅₀ and extent of inhibition values of anti-HER3IgG in SK-Br-3, BT-474 and MCF7 cells SK-Br-3 pAkt BT-474 pAkt MCF7 pAktIC₅₀ % IC₅₀ % IC₅₀ % MOR# (pM) inhibition (pM) inhibition (pM)inhibition MOR12514 nd nd nd nd nd nd MOR12515 nd nd nd nd nd ndMOR12516 nd nd nd nd nd nd MOR12615 101  86 466 63 815 78 MOR12920 nd ndnd nd nd nd MOR12921 nd nd nd nd nd nd MOR12922 nd nd nd nd nd ndMOR13654 89 92 142 58 244 72 MOR13655 62 86 nd 50 251 79 MOR13656 nd ndnd nd nd nd MOR13657 33 91 586 53 385 75 MOR13658 172  92 461 56 341 81MOR13659 nd nd nd nd nd nd MOR13660 nd nd nd nd nd nd MOR13661 nd nd ndnd nd nd MOR13662 nd nd nd nd nd nd MOR13663 nd nd nd nd nd nd MOR13664nd nd nd nd nd nd MOR13665 nd nd nd nd nd nd MOR13666 78 90 275 50  4972 MOR13667 nd nd nd nd nd nd MOR13668 nd nd nd nd nd nd MOR13669 nd ndnd nd nd nd MOR13670 nd nd nd nd nd nd MOR14537 nd nd nd nd nd ndMOR14538 nd nd nd nd nd nd MOR12603 17 84 137 77 nd nd MOR12604 17 85225 70 235 74 MOR12605 140  84 173 67 533 76 MOR12606  8 85  91 77 nd ndMOR14533 nd nd nd nd nd nd MOR14534 nd nd nd nd nd nd

In summary MOR12514, MOR12515, MOR12516, MOR12615, MOR12920, MOR12921,MOR12922, MOR13654, MOR13655, MOR13656, MOR13657, MOR13658, MOR13659,MOR13660, MOR13661, MOR13662, MOR13663, MOR13664, MOR13665, MOR13666,MOR13667, MOR13668, MOR13669, MOR13670, MOR14537, MOR14538, MOR12603,MOR12604, MOR12605, MOR12606, MOR14533 and MOR14534 are each capable ofinhibiting cellular HER3 activity and downstream signaling in both aligand-dependent and ligand-independent manner.

(vi) Inhibition of Proliferation

Since MOR12514, MOR12515, MOR12516, MOR12615, MOR12920, MOR12921,MOR12922, MOR13654, MOR13655, MOR13656, MOR13657, MOR13658, MOR13659,MOR13660, MOR13661, MOR13662, MOR13663, MOR13664, MOR13665, MOR13666,MOR13667, MOR13668, MOR13669, MOR13670, MOR14537, MOR14538, MOR12603,MOR12604, MOR12605, MOR12606, MOR14533 and MOR14534 are capable ofinhibiting HER3 activity a sub-set were tested for their ability toblock ligand dependent and independent in vitro cell growth (exampledata is shown in FIG. 8, FIG. 9, FIG. 10 and summarized in Table 9). Theanti-HER3 antibodies tested were all effective inhibitors of cellproliferation thus confirming that antibodies that bind D3 or D3-4 arecapable of inhibiting HER3 driven phenotypes.

TABLE 9 Inhibition of proliferation following treatment with anti-HER3IgG in SK-Br-3, BT-474 and MCF7 cells. SK-Br-3 BT-474 MCF7 IC₅₀ % IC₅₀ %IC₅₀ % in- MOR# (pM) inhibition (pM) inhibition (pM) hibition MOR1251444 36 nd nd 317 29 MOR12515 278 36 nd nd 1091 26 MOR12516 2082 34 nd nd492 34 MOR12615 121 40 459 35 2537 42 MOR12920 2910 32 nd nd 1921 22MOR12921 432 42 nd nd 2310 31 MOR12922 709 36 nd nd 467 27 MOR13654 13634 632 27 nd nd MOR13655 74 39 141 31 86 46 MOR13656 nd nd nd nd nd ndMOR13657 179 39 473 30 nd nd MOR13658 191 42 423 34 174 49 MOR13659 ndnd nd nd nd nd MOR13660 nd nd nd nd nd nd MOR13661 nd nd nd nd nd ndMOR13662 nd nd nd nd nd nd MOR13663 nd nd nd nd nd nd MOR13664 nd nd ndnd nd nd MOR13665 nd nd nd nd nd nd MOR13666 870 39 1120  31 nd ndMOR13667 nd nd nd nd nd nd MOR13668 nd nd nd nd nd nd MOR13669 nd nd ndnd nd nd MOR13670 nd nd nd nd nd nd MOR14537 47 48 nd nd nd nd MOR1453881 53 nd nd nd nd MOR12603 34 36 136 37 58 44 MOR12604 15 42 nd nd 73 39MOR12605 0.01 29 nd nd 28 45 MOR12606 nd 36 127 40 52 39 MOR14533 26 46nd nd nd nd MOR14534 27 40 nd nd nd nd(vii) In Vivo Inhibition of Tumor Growth

To determine the in vivo activity of the described anti-HER3 antibodies,MOR12606 and MOR13655 were tested for anti-tumor activity in both BxPC3and BT-474 tumor models. Repeated dosing of the BxPC3 model usingMOR12606 or MOR13655 yielded 25% regression and 5% T/C, respectivelyFIG. 11A).

Single agent treatment of the HER2-driven BT474 model with eitherMOR12606 or MOR13655 resulted in 53% or 46% T/C, respectively (FIG.11B).

We also investigated the effect of combining two HER3-targetedantibodies that bind two distinct, non-overlapping epitopes. Repeateddosing of the BT474 model with a combination of MOR10703 and MOR12606yielded 7% T/C (FIG. 12).

INCORPORATION BY REFERENCE

All references cited herein, including patents, patent applications,papers, text books, and the like, and the references cited therein, tothe extent that they are not already, are hereby incorporated herein byreference in their entirety.

EQUIVALENTS

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The foregoingdescription and examples detail certain preferred embodiments of theinvention and describe the best mode contemplated by the inventors. Itwill be appreciated, however, that no matter how detailed the foregoingmay appear in text, the invention may be practiced in many ways and theinvention should be construed in accordance with the appended claims andany equivalents thereof.

1. An isolated antibody or fragment thereof that recognizes a non-linearepitope of a HER3 receptor, wherein the non-linear epitope comprisesamino acid residues within domain 3 of the HER3 receptor, wherein theantibody or fragment thereof binds to a binding surface comprising atleast one amino acid residue selected from binding surface B, andwherein the antibody or fragment thereof blocks both ligand-dependentand ligand-independent signal transduction.
 2. The isolated antibody orfragment thereof of claim 1, wherein binding surface B comprises atleast one amino acid residue selected from amino acid residues 335-342,398, 400, 424-428, 431, 433-434 and
 455. 3. The isolated antibody orfragment thereof of claim 1, wherein the antibody or fragment furtherbinds to binding surface A.
 4. The isolated antibody or fragment thereofof claim 3, wherein binding surface A comprises at least one amino acidresidue selected from the group consisting of amino acid residues362-376.
 5. An isolated antibody or fragment thereof that recognizes anon-linear epitope of a HER3 receptor, wherein the non-linear epitopecomprises amino acid residues within domain 3 of the HER3 receptor,wherein the antibody or fragment thereof binds to a binding surfacecomprising at least one amino acid residue selected from binding surfaceA and at least one amino acid residue selected from binding surface B,and wherein the antibody or fragment thereof blocks bothligand-dependent and ligand-independent signal transduction.
 6. Theisolated antibody or fragment thereof of claim 5, wherein the antibodyor fragment thereof blocks HER3 ligand binding on the HER3 receptor. 7.The isolated antibody or fragment thereof of claim 6, wherein the HER3ligand is selected from the group consisting of neuregulin 1 (NRG),neuregulin 2, betacellulin, heparin-binding epidermal growth factor, andepiregulin.
 8. The isolated antibody or fragment thereof of claim 5,wherein the antibody or fragment thereof has any one of thecharacteristics selected from the group consisting of binding to theinactive state of the HER3 receptor, preventing HER3 adopting an activeconformation due to steric hindrance between the antibody or fragmentthereof and domains of HER3, preventing HER3 adopting an activeconformation by reducing the degree of flexibility in domain 3, inducinga conformational change in domain 3 residues 371-377 that prevents HER3from adopting an active conformation, destabilizing HER3 such that it issusceptible to degradation, accelerating down regulation of cell surfaceHER3, and generating an un-natural HER3 dimer that is susceptible toproteolytic degradation or unable to dimerize with other receptortyrosine kinases.
 9. The isolated antibody or fragment thereof of claim5, wherein the binding surface A comprises amino acid residues 362-376.10. The isolated antibody or fragment thereof of claim 5, wherein thebinding surface B comprises amino acid residues 335-342, 398, 400,424-428, 431, 433-434 and
 455. 11. The isolated antibody of claim 5,wherein the non-linear epitope comprises amino acid residues 335-342,362-376, 398, 400, 424-428, 431, 433-434 and 455 (within domain 3), or asubset thereof.
 12. The isolated antibody of claim 5, wherein the VH ofthe antibody or fragment thereof binds to at least one of the followingHER3 residues: Ile365, Thr366, Asn369, Gly370, Asp371, Pro372, Trp373,His374, Lys375, Gln400, and Lys434.
 13. The isolated antibody of claim5, wherein the VL of the antibody or fragment thereof binds to at leastone of the following HER3 residues: Gly335, Ser336, Gly337, Ser338,Phe340, Gln341, Asp362, Leu364, Ile365, Thr366, His374, Ile376, Asn398,Gln400, Tyr424, Asn425, Arg426, Phe428, Leu431, Met433, Lys434, Tyr455.14. The isolated antibody or fragment of claim 5, wherein binding of theantibody or fragment thereof to the HER3 receptor in the absence of aHER3 ligand reduces ligand-independent formation of a HER2-HER3 proteincomplex in a cell which expresses HER2 and HER3.
 15. The isolatedantibody or fragment thereof of claim 5, wherein the antibody orfragment thereof inhibits phosphorylation of HER3 as assessed by a HER3ligand-independent phosphorylation assay.
 16. The isolated antibody orfragment thereof of claim 15, wherein the HER3 ligand-independentphosphorylation assay uses HER2 amplified cells, wherein the HER2amplified cells are SK-Br-3 cells and BT-474.
 17. The isolated antibodyor fragment of claim 5, wherein binding of the antibody or fragmentthereof to the HER3 receptor in the presence of a HER3 ligand reducesligand-dependent formation of a HER2-HER3 protein complex in a cellwhich expresses HER2 and HER3.
 18. The isolated antibody or fragmentthereof of claim 5, wherein the antibody or fragment thereof inhibitsphosphorylation of HER3 as assessed by HER3 ligand-dependentphosphorylation assay.
 19. The isolated antibody or fragment thereof ofclaim 18, wherein the HER3 ligand-dependent phosphorylation assay usesstimulated MCF7 cells in the presence of neuregulin (NRG).
 20. Theisolated antibody or fragment thereof of claim 5, wherein the antibodyis selected from the group consisting of a monoclonal antibody, apolyclonal antibody, a chimeric antibody, a humanized antibody, and asynthetic antibody.
 21. An isolated antibody or fragment thereof thatrecognizes an epitope of a HER3 receptor, wherein the epitope comprisesamino acid residues within domains 3-4 of the HER3 receptor, and whereinthe antibody or fragment thereof blocks both ligand-dependent andligand-independent signal transduction.
 22. The isolated antibody ofclaim 21, wherein the epitope comprises at least one amino acid residueselected from the group consisting of amino acid residues: 329-498(domain 3) of SEQ ID NO: 1, and at least one amino acid residue selectedfrom the group consisting of amino acid residues 499-642 (domain 4) ofSEQ ID NO:
 1. 23. The isolated antibody of claim 21, wherein the epitopecomprising amino acid residues within domains 3-4 is selected from thegroup consisting of a linear epitope, a non-linear epitope, and aconformational epitope.
 24. The isolated antibody of claim 21, whereinbinding of the antibody or fragment thereof to the HER3 receptor in theabsence of a HER3 ligand reduces ligand-independent formation of aHER2-HER3 protein complex in a cell which expresses HER2 and HER3. 25.The isolated antibody or fragment thereof of claim 21, wherein theantibody or fragment thereof inhibits phosphorylation of HER3 asassessed by a HER3 ligand-independent phosphorylation assay.
 26. Theisolated antibody or fragment thereof of claim 25, wherein the HER3ligand-independent phosphorylation assay uses HER2 amplified cells,wherein the HER2 amplified cells are SK-Br-3 cells and BT-474.
 27. Theisolated antibody or fragment thereof of claim 21, wherein binding ofthe antibody or fragment thereof to the HER3 receptor in the presence ofa HER3 ligand reduces ligand-dependent formation of a HER2-HER3 proteincomplex in a cell which expresses HER2 and HER3.
 28. The isolatedantibody or fragment thereof of claim 21, wherein the antibody orfragment thereof inhibits phosphorylation of HER3 as assessed by HER3ligand-dependent phosphorylation assay.
 29. The isolated antibody orfragment thereof of claim 28, wherein the HER3 ligand-dependentphosphorylation assay uses stimulated MCF7 cells in the presence ofneuregulin (NRG).
 30. An isolated antibody or fragment thereof to a HER3receptor, having a dissociation (K_(D)) of at least 1×10⁷ M⁻, 10⁸ M⁻¹,10⁹ M⁻¹, 10¹⁰ M⁻¹, 10¹¹ M⁻¹, 10¹² M⁻¹, 10¹³ M⁻¹, wherein the antibody orfragment thereof blocks both ligand-dependent and ligand-independentsignal transduction.
 31. The isolated antibody or fragment thereof ofclaim 30, wherein the antibody or fragment thereof inhibitsphosphorylation of HER3 as measured by an in vitro phosphorylation assayselected from the group consisting of phospho-HER3 and phospho-Akt. 32.The isolated antibody or fragment thereof of claim 30, wherein theantibody or fragment thereof binds to the same non-linear epitope withindomain 3 of HER3 as an antibody described in Table
 1. 33. The isolatedantibody or fragment thereof of claim 30, wherein the antibody orfragment thereof, binds to the same amino acid residues within domains3-4 of HER3 as an antibody described in Table
 2. 34. A fragment of anantibody that binds to HER3 selected from the group consisting of; Fab,F(ab₂)′, F(ab)₂′, scFv, VHH, VH, VL, dAbs, wherein the fragment of theantibody blocks both ligand-dependent and ligand-independent signaltransduction.
 35. A pharmaceutical composition comprising an antibody orfragment thereof and a pharmaceutically acceptable carrier.
 36. Thepharmaceutical composition of claim 35, further comprising an additionaltherapeutic agent.
 37. The pharmaceutical composition of claim 36,wherein the additional therapeutic agent is selected from the groupconsisting of an HER1 inhibitor, a HER2 inhibitor, a HER3 inhibitor, aHER4 inhibitor, an mTOR inhibitor and a PI3 Kinase inhibitor.
 38. Thepharmaceutical composition of claim 37, wherein the additionaltherapeutic agent is a HER1 inhibitor selected from the group consistingof Matuzumab (EMD72000), Erbitux®/Cetuximab, Vectibix®/Panitumumab, mAb806, Nimotuzumab, Iressa®/Gefitinib, CI-1033 (PD183805), Lapatinib(GW-572016), Tykerb®/Lapatinib Ditosylate, Tarceva®/Erlotinib HCL(OSI-774), PKI-166, and Tovok®; a HER2 inhibitor selected from the groupconsisting of Pertuzumab, Trastuzumab, MM-111, neratinib, lapatinib orlapatinib ditosylate/Tykerb®; a HER3 inhibitor selected from the groupconsisting of, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888(Amgen), AV-203 (Aveo), MEHD7945A (Genentech), MOR10703 (Novartis) andsmall molecules that inhibit HER3; and a HER4 inhibitor.
 39. Thepharmaceutical composition of claim 37, wherein the additionaltherapeutic agent is a HER3 inhibitor, wherein the HER3 inhibitor isMOR10703.
 40. The pharmaceutical composition of claim 37, wherein theadditional therapeutic agent is an mTOR inhibitor selected from thegroup consisting of Temsirolimus/Torisel®, ridaforolimus/Deforolimus,AP23573, MK8669, everolimus/Affinitor®.
 41. The pharmaceuticalcomposition of claim 37, wherein the additional therapeutic agent is aPI3 Kinase inhibitor selected from the group consisting of GDC 0941,BEZ235, BKM120 and BYL719.
 42. A method of treating a cancer comprisingselecting a subject having an HER3 expressing cancer, administering tothe subject an effective amount of a composition comprising an antibodyor fragment thereof disclosed in Table 1 or Table
 2. 43. The method ofclaim 42, wherein the subject is a human and the cancer is selected fromthe group consisting of breast cancer, colorectal cancer, lung cancer,multiple myeloma, ovarian cancer, liver cancer, gastric cancer, acutemyeloid leukemia, chronic myeloid leukemia, osteosarcoma, squamous cellcarcinoma, peripheral nerve sheath tumors, schwannoma, head and neckcancer, bladder cancer, esophageal cancer, Barretts esophageal cancer,glioblastoma, clear cell sarcoma of soft tissue, malignant mesothelioma,neurofibromatosis, renal cancer, and melanoma, prostate cancer, benignprostatic hyperplasia (BPH), gynacomastica, and endometriosis.